WorldWideScience

Sample records for stromal tumors current

  1. Current management and prognostic features for gastrointestinal stromal tumor (GIST

    Directory of Open Access Journals (Sweden)

    Lamba Gurpreet

    2012-06-01

    Full Text Available Abstract Stromal or mesenchymal neoplasms affecting the gastrointestinal (GI tract have undergone a remarkable evolution in how they are perceived, classified, approached, diagnosed and managed over the last 30 years. Gastrointestinal stromal tumors (GIST account for approximately 1% to 3% of all malignant GI tumors. The clinical features can vary depending on the anatomic location, size and aggressiveness of the tumor. Metastatic GIST represents a successful example of molecular targeted therapy. In this comprehensive review, we discuss the epidemiology, clinical features and diagnostic modalities for GIST. We also describe treatment options for early stage, locally advanced and metastatic GIST. Indications for neoadjuvant and adjuvant therapy along with duration of therapy are also explained. A brief discussion of latest biomarkers and updates from recent meetings is also provided.

  2. GASTROINTESTINAL STROMAL TUMOR (GIST

    Directory of Open Access Journals (Sweden)

    Luigi eTornillo

    2014-11-01

    Full Text Available Gastrointestinal stromal tumors 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 CKIT and PDGFRA and that these mutations are strongly predictive for the response to targeted therapy with receptor tyrosine kinase 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, 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.

  3. Current concepts in non-gastrointestinal stromal tumor soft tissue sarcomas: A primer for radiologists

    Energy Technology Data Exchange (ETDEWEB)

    Baheti, Akahay D. [Dept. of Radiology, Tata Memorial Centre, Mumbai (India); Tirumani, Harika [Dept. of Radiology, University of Arkansas for Medical Sciences, Little Rock (United States); O' Neill, Alibhe; Jagannathan, Jyothi P. [Dept. of Imaging, Dana-Farber Cancer Institute, Boston (United States)

    2017-01-15

    Non-gastrointestinal stromal tumor (GIST) soft tissue sarcomas (STSs) are a heterogeneous group of neoplasms whose classification and management continues to evolve with better understanding of their biologic behavior. The 2013 World Health Organization (WHO) has revised their classification based on new immunohistochemical and cytogenetic data. In this article, we will provide a brief overview of the revised WHO classification of soft tissue tumors, discuss in detail the radiology and management of the two most common adult non-GIST STS, namely liposarcoma and leiomyosarcoma, and review some of the emerging histology-driven targeted therapies in non-GIST STS, focusing on the role of the radiologist.

  4. Gastrointestinal stromal tumors

    International Nuclear Information System (INIS)

    Sufliarsky, J.

    2011-01-01

    Gastrointestinal stromal tumours (GISTs) are the most common mesenchymal tumours of the digestive tract. Better understanding of the molecular characteristics of GISTs led to the clinical development of imatinib for treating patients with this disease. New immuno markers and mechanisms of primary and secondary resistance were discovered. Adjuvant imatinib in intermediate or high risk GIST has improved the recurrence-free survival. Sunitinib in patients with intolerance or progression on imatinib demonstrated significant improvements in progression-free and overall survival versus placebo. Second-generation tyrosine kinase inhibitors, such as sorafenib, dasatinib, and nilotinib, have shown activity in patients with imatinib- and sunitinib-resistant GIST. (author)

  5. An exceptional collision tumor: gastric calcified stromal tumor and ...

    African Journals Online (AJOL)

    The authors report an exceptional case of collision tumor comprised of a gastric calcified stromal tumor and a pancreatic adenocarcinoma. The pancreatic tumor was detected fortuitously on the histological exam of resection specimen. Key words: Collision tumor, stromal tumor, adenocarcinoma ...

  6. Management of hemorrhage in gastrointestinal stromal tumors: a review.

    Science.gov (United States)

    Liu, Qi; Kong, Fanmin; Zhou, Jianping; Dong, Ming; Dong, Qi

    2018-01-01

    Gastrointestinal stromal tumors (GISTs) are relatively common mesenchymal tumors. They originate from the wall of hollow viscera and may be found in any part of the digestive tract. The prognosis of patients with stromal tumors depends on various risk factors, including size, location, presence of mitotic figures, and tumor rupture. Emergency surgery is often required for stromal tumors with hemorrhage. The current literature suggests that stromal tumor hemorrhage indicates poor prognosis. Although the optimal treatment options for hemorrhagic GISTs are based on surgical experience, there remains controversy with regard to optimum postoperative management as well as the classification of malignant potential. This article reviews the biological characteristics, diagnostic features, prognostic factors, treatment, and postoperative management of GISTs with hemorrhage.

  7. Gastrointestinal Stromal Tumors: A Case Report

    Directory of Open Access Journals (Sweden)

    Palankezhe Sashidharan

    2014-03-01

    Full Text Available 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.

  8. Ghrelin and gastrointestinal stromal tumors.

    Science.gov (United States)

    Zhu, Chang-Zhen; Liu, Dong; Kang, Wei-Ming; Yu, Jian-Chun; Ma, Zhi-Qiang; Ye, Xin; Li, Kang

    2017-03-14

    Ghrelin, as a kind of multifunctional protein polypeptide, is mainly produced in the fundus of the stomach and can promote occurrence and development of many tumors, including gastrointestinal tumors, which has been proved by the relevant researches. Most gastrointestinal stromal tumors (GISTs, about 80%), as the most common mesenchymal tumor, also develop in the fundus. Scientific research has confirmed that ghrelin, its receptors and mRNA respectively can be found in GISTs, which demonstrated the existence of a ghrelin autocrine/paracrine loop in GIST tissues. However, no reports to date have specified the mechanism whether ghrelin can promote the occurrence and development of GISTs. Studies of pulmonary artery endothelial cells in a low-oxygen environment and cardiac muscle cells in an ischemic environment have shown that ghrelin can activate the phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling pathway. Moreover, some studies of GISTs have confirmed that activation of the PI3K/AKT/mTOR pathway can indeed promote the growth and progression of GISTs. Whether ghrelin is involved in the development or progression of GISTs through certain pathways remains unknown. Can we find a new target for the treatment of GISTs? This review explores and summaries the relationship among ghrelin, the PI3K/AKT/mTOR pathway and the development of GISTs.

  9. Drugs Approved for Gastrointestinal Stromal Tumors

    Science.gov (United States)

    This page lists cancer drugs approved by the Food and Drug Administration (FDA) for gastrointestinal stromal tumors (GIST). The list includes generic names and brand names. The drug names link to NCI's Cancer Drug Information summaries.

  10. Sex cord-stromal tumors of the ovary: a comprehensive review and update for radiologists

    Science.gov (United States)

    Horta, Mariana; Cunha, Teresa Margarida

    2015-01-01

    Ovarian sex cord-stromal tumors are infrequent and represent approximately 7% of all primary ovarian tumors. This histopathologic ovarian tumor group differs considerably from the more prevalent epithelial ovarian tumors. Although sex cord-stromal tumors present in a broad age group, the majority tend to present as a low-grade disease that usually follows a nonaggressive clinical course in younger patients. Furthermore, because the constituent cells of these tumors are engaged in ovarian steroid hormone production (e.g., androgens, estrogens, and corticoids), sex cord-stromal tumors are commonly associated with various hormone-mediated syndromes and exhibit a wide spectrum of clinical features ranging from hyperandrogenic virilizing states to hyperestrogenic manifestations. The World Health Organization sex cord-stromal tumor classification has recently been revised, and currently these tumors have been regrouped into the following clinicopathologic entities: pure stromal tumors, pure sex cord tumors, and mixed sex cord-stromal tumors. Moreover, some entities considered in the former classification (e.g., stromal luteoma, stromal tumor with minor sex cord elements, and gynandroblastoma) are no longer considered separate tumors in the current classification. Herein, we discuss and revise the ultrasonography, computed tomography, and magnetic resonance imaging characteristics of the different histopathologic types and clinicopathologic features of sex cord-stromal tumors to allow radiologists to narrow the differential diagnosis when facing ovarian tumors. PMID:26054417

  11. Computed tomography in gastrointestinal stromal tumors

    International Nuclear Information System (INIS)

    Ghanem, Nadir; Altehoefer, Carsten; Winterer, Jan; Schaefer, Oliver; Springer, Oliver; Kotter, Elmar; Langer, Mathias; Furtwaengler, Alex

    2003-01-01

    The aim of this study was to define the imaging characteristics of primary and recurrent gastrointestinal stromal tumors (GIST) in computed tomography with respect to the tumor size. Computed tomography was performed in 35 patients with histologically confirmed gastrointestinal stromal tumors and analyzed retrospectively by two experienced and independent radiologist. The following morphologic tumor characteristics of primary (n=20) and (n=16) recurrent tumors were evaluated according to tumor size, shape, homogeneity, density compared with liver, contrast enhancement, presence of calcifications, ulcerations, fistula or distant metastases and the anatomical relationship to the intestinal wall, and the infiltration of adjacent visceral organs. Small GIST ( 5-10 cm) demonstrated an irregular shape, inhomogeneous density on unenhanced and contrast-enhanced images, a combined intra- and extraluminal tumor growth with aggressive findings, and infiltration of adjacent organs in 9 primary diagnosed and 2 recurrent tumors. Large GIST (>10 cm), which were observed in 8 primary tumors and 11 recurrent tumors, showed an irregular margin with inhomogeneous density and aggressive findings, and were characterized by signs of malignancy such as distant and peritoneal metastases. Small recurrent tumors had a similar appearance as compared with large primary tumors. Computed tomography gives additional information with respect to the relationship of gastrointestinal stromal tumor to the gastrointestinal wall and surrounding organs, and it detects distant metastasis. Primary and recurrent GIST demonstrate characteristic CT imaging features which are related to tumor size. Aggressive findings and signs of malignancy are found in larger tumors and in recurrent disease. Computed tomography is useful in detection and characterization of primary and recurrent tumors with regard to tumor growth pattern, tumor size, and varied appearances of gastrointestinal stromal tumors, and indirectly

  12. Gastrointestinal Stromal Tumor: Diagnosis and Prognosis

    International Nuclear Information System (INIS)

    Martin, M. T.; Olmedilla, P.; Gonzalez, S.; Oliver, J. M.

    2003-01-01

    Gastrointestinal stromal tumors (GIST) are mesenquimal tumors derived from cell precursors. They have the capacity for myogenic and neurogenic differentiation and are characterized by expression of KIT protein /tyrosine kinase growth factor). Clinically, they exhibit various biological behaviors. We present 8 cases of GIST, describing both their radiological manifestation through computerized tomography (CT) and most accepted criteria for benignity and malignancy. We also describe the response of one meta statically diagnosed tumor to tyrosine kinase inhibitor. (Author) 9 refs

  13. Ovarian Sex Cord-Stromal Tumors.

    Science.gov (United States)

    Schultz, Kris Ann P; Harris, Anne K; Schneider, Dominik T; Young, Robert H; Brown, Jubilee; Gershenson, David M; Dehner, Louis P; Hill, D Ashley; Messinger, Yoav H; Frazier, A Lindsay

    2016-10-01

    Ovarian sex cord-stromal tumors are clinically significant heterogeneous tumors that include several pathologic types. These tumors are often found in adolescents and young adults and can present with hormonal manifestations as well as signs and symptoms of a pelvic mass. Serum tumor markers may assist in preoperative diagnosis and surveillance. Several subtypes are associated with genetic predisposition, including those observed in patients with Peutz-Jegher syndrome. Recent studies have elucidated the relationship between Sertoli-Leydig cell tumors and DICER1 mutations. When classified as International Federation of Gynecology and Obstetrics stage Ia, most subtypes may be treated with surgery alone. Higher stage or recurrent tumors have variable prognoses that range from a usually rapid course in poorly differentiated Sertoli-Leydig cell tumor to an often prolonged course in adult granulosa cell tumors. New understanding of the molecular pathogenesis of these tumors may pave the way for novel therapeutics.

  14. Sclerosing Stromal Tumor of Ovary: A Case Report

    Directory of Open Access Journals (Sweden)

    Menka Khanna

    2012-01-01

    Full Text Available Sclerosing stromal tumor (SST is an extremely rare and distinctive sex cord stromal tumor which occurs predominantly in the second and third decades of life. We report a case of a 32-year-old woman who developed a sclerosing stromal tumor of ovary and presented with irregular menstruation and pelvic pain. Her hormonal status was normal but CA-125 was raised. She was suspected to have a malignant tumor on computed tomography and underwent bilateral salpingo-oopherectomy. It is therefore necessary to keep in mind the possibility of sclerosing stromal tumor in a young woman.

  15. Gastrointestinal Stromal Tumor – An Evolving Concept

    Science.gov (United States)

    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

  16. Gastrointestinal stromal tumors: CT and MRI findings

    Energy Technology Data Exchange (ETDEWEB)

    Sandrasegaran, Kumaresan; Rydberg, Jonas; Akisik, Fatih M. [Indiana University Medical Center, Department of Radiology, Indianapolis, IN (United States); Rajesh, Arumugam [United Leicester Hospitals, Department of Radiology, Leicester (United Kingdom); Rushing, Daniel A. [Indiana University Medical Center, Department of Oncology, Indianapolis, Indiana (United States); Henley, John D. [Indiana University Medical Center, Department of Pathology, Indianapolis, Indiana (United States)

    2005-07-01

    The objective of this study was to report the CT and MRI appearances of primary and metastatic gastrointestinal stromal tumor (GIST). The clinical and imaging findings of 31 patients with histological and immunohistochemical diagnosis of GIST were reviewed. The CT and MRI findings were assessed independently for size, location, enhancement characteristics, and pattern of metastatic disease. The tumors were of enteric (n=13), gastric (n=12), duodenal (n=2), and rectal (n=3) origin. In one case the primary site was the mesentery, without involvement of bowel. Primary tumors were typically exophytic (79%), larger than 5 cm (84%), and inhomogeneously enhancing (84%). Central necrosis of all tumors (37%) and aneurysmal dilation of enteric tumors (33%) were less common. Metastases were most commonly to mesentery (26%) or liver (32%). Less common findings were ascites (7%) and omental caking (3%). Liver metastases were hypervascular in 92% of patients and rapidly became cystic following therapy with imatinib mesylate (Gleevec; Novartis, East Hanover, NJ, USA). Lung metastases, bowel obstruction, vascular invasion, and significant lymphadenopathy were not seen in any patient. GISTs have some specific CT findings which could help differentiate them from other gastrointestinal tumors. Liver metastases became cystic following therapy, mimicking simple cysts. MRI was better than single-phase CT for assessing liver metastases, while CT was more sensitive for mesenteric metastases. (orig.)

  17. Update on gastrointestinal stromal tumors for radiologists

    Energy Technology Data Exchange (ETDEWEB)

    Tirumani, Sree Harsha; O' Neill, Alibhe; Jagannathan, Jyothi P. [Dept. of Imaging, Dana-Farber Cancer Institute, Boston (United States); Baheti, Akahay D. [Dept. of Radiology, Tata Memorial Centre, Mumbai (India); Tirumani, Harika [Dept. of Radiology, University of Arkansas for Medical Sciences, Little Rock (United States)

    2017-01-15

    The management of gastrointestinal stromal tumors (GISTs) has evolved significantly in the last two decades due to better understanding of their biologic behavior as well as development of molecular targeted therapies. GISTs with exon 11 mutation respond to imatinib whereas GISTs with exon 9 or succinate dehydrogenase subunit mutations do not. Risk stratification models have enabled stratifying GISTs according to risk of recurrence and choosing patients who may benefit from adjuvant therapy. Assessing response to targeted therapies in GIST using conventional response criteria has several potential pitfalls leading to search for alternate response criteria based on changes in tumor attenuation, volume, metabolic and functional parameters. Surveillance of patients with GIST in the adjuvant setting is important for timely detection of recurrences.

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

    Science.gov (United States)

    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.

  19. Nuclear morphometric analysis in gastrointestinal stromal tumors: a preliminary study.

    Science.gov (United States)

    Ozdamar, Sükrü Oğuz; Bektaş, Sibel; Erdem Ozdamar, Sevim; Gedikoğlu, Gökhan; Doğan Gün, Banu; Bahadir, Burak

    2007-06-01

    Gastrointestinal stromal tumors are considered a specialized group of mesenchymal neoplasms. In this study, the histomorphologic and immunohistochemical features of gastrointestinal stromal tumors are compared with nuclear morphometric results. Morphometric nuclear parameters such as mean area, mean roundness factor, mean form ellipse, mean length and mean perimeter were evaluated in hematoxylin and eosin stained slides of 22 gastrointestinal stromal tumors (9 benign and 13 malignant) by using a computer-assisted image analysis system. Morphometric results were compared with tumor behavior and tumor size, the presence of necrosis, mitotic index, and immunohistochemical expressions of p53 and proliferating cell nuclear antigen. We found that tumor necrosis was correlated with mean nuclear roundness factor, mean nuclear form ellipse, mean nuclear length and mean nuclear perimeter (pmorphometric features and gastrointestinal stromal tumor behavior, tumor size, or index of proliferating cell nuclear antigen and p53 expressions (p>0.05). In this preliminary study, the relative concordance of the morphometric results and general histomorphologic data exhibited the importance of nuclear morphometric analysis in gastrointestinal stromal tumors. Studies including larger series of cases investigating detailed nuclear morphometric analysis of gastrointestinal stromal tumors are needed.

  20. Synchronous Acromegaly and Gastrointestinal Stromal Tumor: A Case Report

    Directory of Open Access Journals (Sweden)

    Hüsniye Başer

    2014-06-01

    Full Text Available Acromegaly is a rare endocrine disorder characterized by the manifestations of sustained hypersecretion of growth hormone and concomitant elevations in circulating concentrations of insulin-like growth factor-1. It has been reported that patients with acromegaly are at the increased risk of developing malignant tumors, particularly colorectal cancer. Gastrointestinal stromal tumors are mesenchymal tumors of the digestive tract. An association between gastrointestinal stromal tumors and insulin-like growth factor system has been reported. Here, we report a patient diagnosed with synchronous acromegaly and gastrointestinal stromal tumor. A 59-year-old man with iron deficiency anemia presented with enlarged hands, coarse facial feature and several skin tags. Thyroid function tests were within normal range. Growth hormone was 5.14 ng/mL, insulin-like growth factor-1 was 820 ng/mL, and no growth hormone suppression was observed on 75g oral glucose tolerance test. Pituitary magnetic resonance imaging revealed microadenoma, and the patient was diagnosed with acromegaly. Upper gastrointestinal tract endoscopy revealed an ulcerovegetan mass in the duodenum and the results of the histopathologcal analysis was consistent with gastrointestinal stromal tumor. The association of synchronous and asynchronous gastrointestinal stromal tumors with other malignancies have been reported. The most common accompanying neoplasms are colorectal and gastric adenocarcinomas, as well as pancreatic tumors. However, in the literature, the number of reported cases of synchronous acromegaly and gastrointestinal stromal tumor are limited, and there are no sufficient data on this association. Turk Jem 2014; 2: 52-55

  1. [Gatrointestinal stromal tumor: a case report].

    Science.gov (United States)

    Fernández–Ruiz, M; Cabezas–Palacios, M N; Rodríguez–Zarco, E; Tato–Varela, S

    2016-09-01

    Gastrointestinal stromal tumors are the most common mesenquimal neoplasms of the gastrointestinal tract. A preoperative diagnose of GIST it is very difficult to make, but up to 5% of the cases initially appear as a pelvic mass. 45-year-old patient attended in medical service by unspecific pain in the lower abdomen of several weeks of evolution. The abdominopelvic tomography evidence collection of 9×8 cm above of the uterus and sigma’s right with air in the cavity, it is was compatible with pelvic abscess. Due to increased pain, we realized emergency exploratory laparotomy, which showed a 14 cm tumor, dependent of the small intestine, without ascites or involvement other organs of the digestive or reproductive tract. The excision of the tumor was successfully (non intraoperative rupture). The pathological study reported a bowel piece of 20 cm, in which a tumor of 14 cm with large central cavitation was identified. Histologically showed diffuse growth pattern and neoplastic epithelioid cells with low rate of mitosis (mitosis 1-2/5 mm2). The immunohistochemistry test reports strong expression of DOG-1 and focal expression in CD117 (c-kit), with very low proliferation index (Ki67). The molecular pathology study identified a mutation in exon 11, codon 557-558, the c-kit gene in the p.W557_K558del position. We use imatinib (400 mg/24 h) from the second month after surgery. Today keep in treatment, and clinical and laboratories following every month: in addition, to CT scans scheduled every 6 months.

  2. Primary omental Gastrointestinal stromal tumor (GIST

    Directory of Open Access Journals (Sweden)

    Hirahara Nobutsune

    2007-06-01

    Full Text Available Abstract Background We report herein a rare case of primary omental gastrointestinal stromal tumor (GIST. Case presentation A 65 year-old man was referred to our hospital with a huge abdominal mass occupying the entire left upper abdomen as shown by sonography. On computed tomography (CT, this appeared as a heterogeneous low-density mass with faint enhancement. Abdominal angiography revealed that the right gastroepiploic artery supplied the tumor. With such an indication of gastric GIST, liposarcoma, leiomyosarcoma or mesothelioma laparotomy was performed and revealed that this large mass measured 20 × 17 × 6 cm, arising from the greater omentum. It was completely resected. Histopathologically, it was composed of proliferating spindle and epithelioid cells with an interlacing bundle pattern. Immunohistochemically, the tumor was positive for myeloid stem cell antigen (CD34, weakly positive for c-KIT (CD117 and slightly positive for neuron-specific enolase (NSE, but negative for cytokeratin (CK, alpha-smooth muscle actin (SMA and S-100 protein. A mutation was identified in the platelet-derived growth factor alpha (PDGFRA juxtamembrane domain (exon 12, codon561 and the tumor was diagnosed as an omental GIST. The postoperative course was uneventful. The patient is treated by Glevec® and is alive well with no sign of relapse. Conclusion Our case demonstrated a weak immunohistochemical expression of c-kit (CD117 and a point mutation in PDGFRA exon 12 resulting in an Asp for Val561 substitution. Imatinib therapy as an adjuvant to complete resection has been carried out safely. Because of the rarity of primary omental GISTs, it is inevitable to analyze accumulating data from case reports for a better and more detailed understanding of primary omental GISTs.

  3. MR findings of ovarian tumors with hormonal activity, with emphasis on tumors other than sex cord-stromal tumors

    International Nuclear Information System (INIS)

    Tanaka, Yumiko Oishi; Saida, Tsukasa Sasaki; Minami, Rie; Yagi, Takako; Tsunoda, Hajime; Yoshikawa, Hiroyuki; Minami, Manabu

    2007-01-01

    Sex cord-stromal tumors including granulosa cell tumor, thecoma, Sertoli stromal cell tumor and steroid cell tumor are noted for their hormonal activity. However, there are many kinds of ovarian tumors other than sex cord-stromal tumors and tumor-like conditions with endocrine manifestations. Cross-sectional imaging, especially MR, can provide precise features of ovarian tumors and uterine morphological change even in a clinically latent excess of estrogen. In this article, we demonstrate typical imaging findings of ovarian tumors with hormonal activity. We also shortly explain the mechanism of the virilization and hyperestrogenism caused by ovarian tumors and tumor-like conditions

  4. Endometrial stromal tumors with sex cord-like elements: a case report

    African Journals Online (AJOL)

    Endometrial stromal nodules are rare. They represent less than a quarter of endometrial stromal tumors. Clement and Scully described as variants of endometrial stromal nodules two types of tumor ressembling ovarian sex cord tumors. Type I is tumor that resembles focally an ovarian sex cord tumor which can be ...

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

    Directory of Open Access Journals (Sweden)

    Kamran P. Sajadi

    2009-01-01

    Full Text Available 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.

  6. Esophageal Gastrointestinal Stromal Tumor: Diagnostic Complexity and Management Pitfalls

    Directory of Open Access Journals (Sweden)

    Charalampos G. Markakis

    2013-01-01

    Full Text Available Introduction. Gastrointestinal stromal tumors of the esophagus are rare. Case Presentation. This is a case of a 50-year-old male patient who was referred to our department complaining of atypical chest pain. A chest computed tomographic scan and endoscopic ultrasound revealed a submucosal esophageal tumor measuring 5 cm in its largest diameter. Suspecting a leiomyoma, we performed enucleation via right thoracotomy. The pathology report yielded a diagnosis of an esophageal gastrointestinal stromal tumor. The patient has shown no evidence of recurrence one year postoperatively. Conclusions. This report illustrates the complexity and dilemmas inherent in diagnosing and treating esophageal GISTs.

  7. Considering the role of radiation therapy for gastrointestinal stromal tumor

    Directory of Open Access Journals (Sweden)

    Corbin KS

    2014-05-01

    Full Text Available Kimberly S Corbin,1 Hedy L Kindler,2 Stanley L Liauw31Department of Radiation Oncology, Memorial Medical Center, Springfield, IL, USA; 2Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL, USA; 3Department of Radiation and Cellular Oncology, University of Chicago, Chicago, IL, USAAbstract: Gastrointestinal stromal tumors (GISTs are rare mesenchymal tumors arising in the gastrointestinal tract. Over the last decade, the management and prognosis of GISTs has changed dramatically with molecular characterization of the c-kit mutation and the adoption of targeted systemic therapy. Currently, the standard of care for resectable tumors is surgery, followed by adjuvant imatinib for tumors at high risk for recurrence. Inoperable or metastatic tumors are treated primarily with imatinib. Despite excellent initial response rates, resistance to targeted therapy has emerged as a common clinical problem, with relatively few therapeutic solutions. While the treatment of GISTs does not commonly include radiotherapy, radiation therapy could be a valuable contributing modality. Several case reports indicate that radiation can control locally progressive, drug-resistant disease. Further study is necessary to define whether radiation could potentially prevent or delay the onset of drug resistance, or improve outcomes when given in combination with imatinib.Keywords: GIST, imatinib, radiotherapy

  8. Imbalances of Chromosomes 4, 9, and 12 are Recurrent in the Thecoma-Fibroma Group of Ovarian Stromal Tumors

    OpenAIRE

    Streblow, Renae C.; Dafferner, Alicia J.; Nelson, Marilu; Fletcher, Mavis; West, William W.; Stevens, Rachel K.; Gatalica, Zoran; Novak, Deborah; Bridge, Julia A.

    2007-01-01

    Traditional cytogenetic studies of ovarian stromal tumors are few, although trisomy 12 has been frequently documented utilizing fluorescence in-situ hybridization (FISH). In the current study, karyotypic analysis of four ovarian stromal tumors and a review of the literature suggested that numerical abnormalities of chromosomes 4 and 9 might also be important, possibly as secondary changes. To determine the frequency of 4, 9, and 12 aneuploidy in a larger group of ovarian tumors, FISH studies ...

  9. Treatment of gastrointestinal stromal tumor (GIST during bariatric surgery

    Directory of Open Access Journals (Sweden)

    Fernando de Barros

    Full Text Available The gastrointestinal stromal tumor (GIST is a rare mesenchymal tumor. One should pay special attention when the GIST comes in obese patients during surgery. The laparoscopic resections with standard techniques, such as gastric bypass, have been described with good results. However, GIST resection associated sleeve gastrectomy for the treatment of obesity is rare, but can be done safely, depending on the location of the tumor.

  10. Gastrointestinal stromal tumor of the anal wall in a Nigerian ...

    African Journals Online (AJOL)

    Documented reports of gastrointestinal stromal tumors (GIST) are relatively few in the sub-Saharan continent. The body of evidence points towards anal wall involvement being a rarity indeed. In this article we document a 61 year old Nigerian man who presented with bleeding per rectum and in whom the histological ...

  11. A Rare Case of Mesenteric Gastrointestinal Stromal Tumor ...

    African Journals Online (AJOL)

    We here report such a rare case of GIST arising from mesentery of small bowel and presenting as acute abdomen. Good surgical clearance ensures good survival whereas incomplete resection results in a high incidence of recurrences with distant metastasis. Keywords: Gastrointestinal stromal tumors, imatinib, mesenteric ...

  12. Multiple gastrointestinal stromal tumors and bilateral pheochromocytoma in neurofibromatosis

    Science.gov (United States)

    Kramer, Klaus; Hasel, Cornelia; Aschoff, Andrik J; Henne-Bruns, Doris; Wuerl, Peter

    2007-01-01

    The coincidence of a gastrointestinal stromal tumor (GIST) and a neuroendocrine tumor (NET) in neurofibromatosis type 1 (NF1) is described only five times within the literature. We report on a 63 year old Caucasian female with the rare condition of neurofibromatosis type 1 coinciding with recurrent gastrointestinal stromal tumor plus bilateral pheochromocytoma (PCC). After a history of palpitations and dizziness that lasted for years, a left adrenal mass was detected by CT. Laparotomy revealed a pheochromocytoma of the left adrenal gland while an ileoterminal GIST was found incidentally intraoperatively. After six months contralateral PCC and multiple recurrent GIST were resected again. After four years the patient is doing well without any signs of further recurrent tumors. Discussion includes review of the literature. PMID:17659681

  13. Considering the role of radiation therapy for gastrointestinal stromal tumor

    OpenAIRE

    Liauw, Stanley; Corbin,Kimberly S.; Kindler,Hedy

    2014-01-01

    Kimberly S Corbin,1 Hedy L Kindler,2 Stanley L Liauw31Department of Radiation Oncology, Memorial Medical Center, Springfield, IL, USA; 2Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL, USA; 3Department of Radiation and Cellular Oncology, University of Chicago, Chicago, IL, USAAbstract: Gastrointestinal stromal tumors (GISTs) are rare mesenchymal tumors arising in the gastrointestinal tract. Over the last decade, the management and prognosis of GISTs ...

  14. Rare case of gastrointestinal stromal tumor of the anal canal

    Directory of Open Access Journals (Sweden)

    Madhu Kumar

    2013-01-01

    Full Text Available Gastrointestinal stromal tumor (GIST is a rare mesenchymal neoplasm of the gastrointestinal tract. GIST of anal canal is very rare representing only 3% of all anorectal mesenchymal tumors. We report an extremely rare case of GIST of the anal canal in 60-years-old man with history of irregular bowel habits with dark colored stool mixed with blood and constipation from 6 month. Diagnosis was made on the basis of histomorphological and immunohistochemical examination.

  15. Alfa-fetoprotein secreting ovarian sex cord-stromal tumor

    Directory of Open Access Journals (Sweden)

    Kusum D Jashnani

    2013-01-01

    Full Text Available Ovarian sex cord-stromal tumors are relatively infrequent neoplasms that account for approximately 8% of all primary ovarian tumors. They are a heterogeneous group of neoplasms composed of cells derived from gonadal sex cords (granulosa and Sertoli cells, specialized gonadal stroma (theca and Leydig cells, and fibroblasts. They may show androgenic or estrogenic manifestations. We report such a tumor associated with markedly raised serum alpha-fetoprotein (AFP levels in a young female presenting with a mass and defeminising symptoms. Serum AFP levels returned to normal on removal of tumor.

  16. Gastric Schwannoma mimicking malignant gastrointestinal stromal tumor and misdiagnosed by (18)F-FDG PET/CT.

    Science.gov (United States)

    Zhang, Yiqiu; Li, Beilei; Cai, Liang; Hou, Xiaoguang; Shi, Hongcheng; Hou, Jun

    2015-01-01

    Gastric Schwannoma is a rare benign mesenchymal tumor that accounts for only 0.2% of all gastric tumors. The current study presents a case of gastric Schwannoma misdiagnosed as malignant gastrointestinal stromal tumor (GIST) by esophagogastroduodenoscopy, endoscopic ultrasonography, and contrast-enhanced or not enhanced and (18)F-FDG PET/CT imaging.

  17. CD34-positive stromal cells and alpha-smooth muscle actin-positive stromal cells in the tumor capsule of skin sweat gland neoplasms.

    Science.gov (United States)

    Nakayama, Hirofumi; Enzan, Hideaki; Miyazaki, Eriko; Moriki, Toshiaki; Toi, Makoto; Zhang, Yanhu

    2002-01-01

    To elucidate the roles of CD34-positive stromal cells and alpha-smooth muscle actin-positive stromal cells at the tumor border of skin sweat gland neoplasms, we examined expression of stromal cell markers in the tumor capsule of 19 skin sweat gland neoplasms (16 mixed tumors of the skin and three nodular hidradenomas) using monoclonal antibodies to CD34, CD31, cytokeratin 14 (CK14), alpha-smooth muscle actin (ASMA) and high molecular weight caldesmon (HCD). We regarded CD34-positive, CD31-, CK14-, ASMA- and HCD-negative stromal cells to be CD34-positive stromal cells, and ASMA-positive, HCD-, CK14-, CD34- and CD31-negative stromal cells to be ASMA-positive stromal cells. CD34-positive stromal cells were detected in the tumor capsule of all 19 of the tumors examined. In nine of the 16 mixed tumors (56%) and all of the three nodular hidradenomas, ASMA-positive stromal cells were detected at the immediate inner side of the CD34-positive stromal cell layers. These results indicate that cellular components in the tumor capsules of mixed tumors of the skin and nodular hidradenomas are CD34-positive stromal cells and ASMA-positive stromal cells, and suggest that stromal cells of these two cell types are associated with tumor capsule formation of skin sweat gland neoplasms.

  18. The DREAM complex in antitumor activity of imatinib mesylate in gastrointestinal stromal tumors.

    Science.gov (United States)

    DeCaprio, James A; Duensing, Anette

    2014-07-01

    Although most gastrointestinal stromal tumors respond well to treatment with the small molecule kinase inhibitor imatinib mesylate (Gleevec), complete remissions are rare and the majority of patients achieve disease stabilization. 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. Although imatinib induces apoptosis in a subset of gastrointestinal stromal tumor cells, it leads to 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 (DP, p130/RBL2, E2F4 and MuvB), 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 dual-specificity tyrosine phosphorylation-regulated kinase 1A was shown to enhance imatinib-induced gastrointestinal stromal tumor cell death. Targeting the DREAM complex and imatinib-induced quiescence could provide opportunities for future therapeutic interventions toward more efficient imatinib responses.

  19. A novel complex KIT mutation in a gastrointestinal stromal tumor of the vermiform appendix.

    Science.gov (United States)

    Vassos, Nikolaos; Agaimy, Abbas; Günther, Klaus; Hohenberger, Werner; Schneider-Stock, Regine; Croner, Roland S

    2013-04-01

    Gastrointestinal stromal tumors of the vermiform appendix are rare. To date, only 11 cases have been reported in the English literature. Here, we present a new case of appendiceal gastrointestinal stromal tumor associated with complete situs inversus. A 48-year-old man was operated on due to appendicitis-like symptoms. Laparotomy revealed a ruptured conglomerate tumor in the lower abdomen associated with extensive peritoneal adhesions. Histology showed a spindle cell gastrointestinal stromal tumor with prominent sclerosis and calcification without low mitotic activity. The tumor cells expressed strongly CD117 and CD34. The mutation analysis revealed a heterozygous deletion/insertion involving exon 11 of KIT (pK558_V559delNNins). Because the tumor was ruptured intraoperatively, a high risk was assigned according to the revised National Institute of Health criteria and adjuvant therapy with imatinib mesylate was recommended. The patient is currently alive without evidence of progression 27 months after surgery. Copyright © 2013 Elsevier Inc. All rights reserved.

  20. Gastrointestinal stromal tumor of the anal canal: An unusual presentation

    Directory of Open Access Journals (Sweden)

    Chhanda Das

    2017-01-01

    Full Text Available Gastrointestinal stromal tumors (GISTs are the most common mesenchymal neoplasm of the gastrointestinal tract. The most common site is stomach, followed by small intestine, colon, and esophagus. However, GIST from the anal canal is an extremely rare tumor. Here, we report an extremely rare case of GIST of the anal canal in a 40-year-old female with a history of irregular bowel habits mixed with blood and constipation for 4 months. Diagnosis was made on the basis of histopathological and immunohistochemical examination.

  1. Gastric schwannoma: a benign tumor often misdiagnosed as gastrointestinal stromal tumor

    Directory of Open Access Journals (Sweden)

    Apurva S. Shah

    2015-10-01

    Full Text Available 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.

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

    Science.gov (United States)

    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.

  3. Pathology and molecular biology of gastrointestinal stromal tumors (GIST)

    International Nuclear Information System (INIS)

    Schildhaus, H.U.; Merkelbach-Bruse, S.; Buettner, R.; Wardelmann, E.

    2009-01-01

    Gastrointestinal stromal tumors (GIST) show an aggressive behavior with metastases and recurrences in up to 50% of cases. They can be clearly distinguished from other mesenchymal tumors by immunohistochemistry in the vast majority of cases. Of the tumors 85% carry somatic activating mutations in the receptor tyrosine kinases KIT or PDGFRA. The detection of these molecular events has changed the treatment of inoperable and metastatic GISTs dramatically as up to 80% of tumors respond well to tyrosine kinase inhibitors. This treatment has become the gold standard in the last few years with only few side effects. Knowledge of the underlying KIT or PDGFRA mutation is both relevant for the prognosis and treatment response. (orig.) [de

  4. Promising novel therapeutic approaches in the management of gastrointestinal stromal tumors.

    Science.gov (United States)

    Szucs, Zoltan; Thway, Khin; Fisher, Cyril; Bulusu, Ramesh; Constantinidou, Anastasia; Benson, Charlotte; van der Graaf, Winette Ta; Jones, Robin L

    2017-01-01

    Primary and secondary resistance to currently available licensed tyrosine kinase inhibitors poses a real clinical challenge in the management of advanced gastrointestinal stromal tumors. Within the frame of early phase clinical trials novel systemic treatments are currently being evaluated to target both the well explored and novel emerging downstream effectors of KIT and PDGFRA signaling. Alternative therapeutic approaches also include exploring novel inhibitors of the KIT/PDGFRA receptors, immune checkpoint and cyclin-dependent kinase inhibitors. The final clinical trial outcome data for these agents are highly anticipated. Integration of new diagnostic techniques into routine clinical practice can potentially guide tailored delivery of agents in the treatment of a highly polyclonal, heterogeneous disease such as heavily pretreated advanced gastrointestinal stromal tumor.

  5. Incidentally detected gastrointestinal stromal tumor: A case report

    Directory of Open Access Journals (Sweden)

    Tolga Canbak

    2017-12-01

    Full Text Available Gastrointestinal stromal tumors (GIST are mesenchymal tumors located primarily in the gastrointestinal tract. We aimed to present a case report of GIST incidentally detected during laparoscopic cholecystectomy.A 60-year-old woman was admitted to the emergency room due to abdominal pain for one day. The physical examination revealed sensitivity on the right upper quadrant. In the laboratory examinations, white blood cell count 6,490 k/uL, hemoglobin 12 g/dL, hematocrit 35% and other biochemical tests were normal. Abdominal ultrasound revealed hydropic gallbladder, several gallstones with a maximum diameter of 15 mm and pericholecystic fluid collection was present. Laparoscopic cholecystectomy was planned due to acute cholecystitis. In exploration, beside the presence of acute cholecystitis, a mass of approximately 5 cm, located 15 cm distal to the ligament of Treitz was detected. Laparoscopic cholecystectomy was performed. Conversion to open laparotomy was done; small intestine resection with end-to-end anastomosis was performed. Gastrointestinal stromal tumor with CD117, CD34 and S100 positivity was detected on histopathologic examination.It is thought that GISTs are mesenchymal tumors originating from precursors of Kajal cells. GISTs are usually detected in their 60s. The first option for treatment is surgical resection.

  6. Large Gastrointestinal Stromal Tumor Mimicking A Gynecologic Tumor

    Directory of Open Access Journals (Sweden)

    Sew-Khee Yeat

    2005-06-01

    Conclusion: GISTs express c-kit proteins (CD-117 on immunohistochemistry. They may mimic gynecologic tumors since they share the same pelvic cavity. One should always consider GISTs as part of the differential diagnosis in pelvic tumors.

  7. Gastrointestinal Stromal Tumor: Diagnosis and Prognosis; Tumor estromal gastrointestinal: diagnostico y pronostico

    Energy Technology Data Exchange (ETDEWEB)

    Martin, M. T.; Olmedilla, P.; Gonzalez, S.; Oliver, J. M. [Fundacion Hospital de Alcorcon. Madrid (Spain)

    2003-07-01

    Gastrointestinal stromal tumors (GIST) are mesenquimal tumors derived from cell precursors. They have the capacity for myogenic and neurogenic differentiation and are characterized by expression of KIT protein (tyrosine kinase growth factor). Clinically, they exhibit various biological behaviors. We present 8 cases of GIST, describing both their radiological manifestation through computerized tomography (CT) and most accepted criteria for benignity and malignancy. We also describe the response of one meta statically diagnosed tumor to tyrosine kinase inhibitor. (Author) 9 refs.

  8. Giant Rectal Gastrointestinal Stromal Tumors: A Report of Two Cases

    Directory of Open Access Journals (Sweden)

    C. Dickhoff

    2008-03-01

    Full Text Available Giant gastrointestinal stromal tumors (GISTs of the rectum are rare and often difficult to remove surgically. At the time metastases are found, GISTs are considered to be incurable and until recently no adequate therapy was of any value for these patients. Recently, imatinib was introduced: a signal transducing inhibitor acting specifically on the KIT-tyrosine kinase, which can be used to downsize giant GIST (neo-adjuvant before surgery or induce stable disease in case of metastases with few minor side-effects. Two patients with giant rectal GIST are presented, one of which was treated before the imatinib era, the other when imatinib was available.

  9. Stromal p16 Overexpression in Adult Granulosa Cell Tumors of the Ovary.

    Science.gov (United States)

    Na, Kiyong; Sung, Ji-Youn; Kim, Hyun-Soo

    2017-05-01

    Adult granulosa cell tumor of the ovary is usually diagnosed at an early stage. However, most patients with advanced or recurrent disease will die of the disease due to limited treatment options. Data on the stromal p16 expression of ovarian adult granulosa cell tumors are limited. The aim of this study was to analyze the immunohistochemical p16 expression in the peritumoral stroma of primary and recurrent adult granulosa cell tumors and investigate whether there were significant differences in stromal p16 expression among nonpathological ovaries, benign sex cord-stromal tumors, and adult granulosa cell tumors. This study included 13 and 11 cases of primary and recurrent adult granulosa cell tumors, respectively. Non-pathological ovaries and benign sex cord-stromal tumors showed negative or weak positive expression, whereas most of the adult granulosa cell tumors showed diffuse and moderate-to-strong immunostaining. Primary adult granulosa cell tumors had significantly higher stromal p16 expression levels than nonpathological ovaries and benign sex cord-stromal tumors (padult granulosa cell tumors showed significantly elevated levels of stromal p16 expression compared to primary adult granulosa cell tumors (p=0.032). In contrast, the difference in stromal p16 expression between non-pathological ovaries and benign sex cord-stromal tumors was not statistically significant (p=0.522). Our observations suggest that stromal p16 expression may be involved in the development and progression of ovarian adult granulosa cell tumors. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  10. Perivascular epithelioid cell tumor of the liver coexisting with a gastrointestinal stromal tumor

    DEFF Research Database (Denmark)

    Paiva, Carlos Eduardo; Moraes Neto, Francisco Alves; Agaimy, Abbas

    2008-01-01

    Approximately 10% of patients with gastrointestinal stromal tumors (GIST) develop other neoplasms, either synchronously or metachronously. In this report we describe coexistence of a gastrointestinal stromal tumor and a hepatic perivascular epithelioid cell tumor (PEComa) in a 51-year-old woman...... with no evidence of tuberous sclerosis. A subcapsular hepatic nodule (0.8 cm in diameter) was found during surgery for symptomatic gastric neoplasm (15 cm in diameter) arising from the lesser curvature. Both tumors revealed histomorphological and immunohistochemical features confirming a diagnosis of a small...... incidental hepatic PEComa and a high risky extramural gastric GIST, respectively. The patient remained disease-free 25 mo after surgery with no evidence of tumor recurrence or new neoplasms. To our knowledge, this is the first report of PEComa in a patient with GIST. Hepatic lesions detected synchronously...

  11. [Gastrointestinal stromal tumors: a series of 23 surgically treated cases].

    Science.gov (United States)

    D'Amato, A; Brini, A; Montesani, C; Pronio, A; Chessa, A; Manzi, F; Ribotta, G

    2001-01-01

    The recently introduced new nosological category, Gastro Intestinal Stromal Tumors, brought the Authors to a revision of their series and to a critical analysis of surgical behaviour for the treatment of that pathology. A series of 23 cases of GIST, observed between 1977 and 1999 has been taken into account. In the earlier cases, histopathological classification has been reviewed according to the most used criterions in international scientific literature. 17 of 23 observed tumors were located on the stomach, 4 on the duodenum and 2 on the jejunum. 20 of these cases derived from muscular tissue and 3 cases derived both from muscular and neural tissues. In 7 cases (30%) tumors were accidentally discovered during surgical intervention or diagnostic procedures for other causes. Surgical treatment was performed in all cases and consisted in 6 gastric resections, 14 gastric free-margin excisions, 2 duodenal resections and 1 jejunal resection. The follow-up (performed on 18 patients, with a minimum of 1 year, a maximum of 17 years and a median of 6 years) showed 2 deaths (11%) due to oncological causes, while 2 of the patients (11%) died for other causes. The only treatment for that group of tumors is, at the moment, surgery. Although that kind of neoplasms has mainly non-aggressive biological behaviour, a radical resection must be performed, due to the absence of macroscopic criterions to help distinguishing, during surgical intervention, aggressive tumors from non-aggressive ones.

  12. Stromal tumor presents as a large extragastrointestinal mass in the abdominal cavity

    OpenAIRE

    Chou, Chung-Kai; Hsu, Chia-Yang; Chan, Che-Chang; Li, Anna; Lin, Han-Chieh

    2017-01-01

    Gastrointestinal stromal tumors are nonepithelial neoplasms of the gastrointestinal tract and have been increasingly recognized in recent years. In contrast, stromal tumor outside the gastrointestinal tract is not frequently found. Here, we present a 57-year-old male patient who had abdominal fullness for several months. It was caused by a 23-cm heterogeneous tumor mass that was successfully removed from the left upper abdominal cavity. The tumor adhered tightly to adjacent organs but postope...

  13. Ovarian Sex Cord-stromal Tumors With Melanin Pigment: Report of a Previously Undescribed Phenomenon.

    Science.gov (United States)

    Taylor, Jennifer; McCluggage, W Glenn

    2017-11-14

    We report 2 ovarian sex cord-stromal tumors, a luteinized adult granulosa cell tumor and a cellular fibroma, with melanin pigment. These occurred in 44 and 61-yr-old patients, respectively. As far as we are aware, melanin pigment has not been described previously in an ovarian sex cord-stromal tumor, although it has been reported in a testicular Sertoli cell tumor. We review ovarian neoplasms containing melanin pigment.

  14. Gastrointestinal stromal tumor of the rectum with scapular metastasis: a case report

    Directory of Open Access Journals (Sweden)

    Selcukbiricik Fatih

    2012-06-01

    Full Text Available Abstract Introduction Gastrointestinal stromal tumors are rare tumors. They commonly metastasize within the abdominal cavity, particularly to the liver. Less commonly, metastases can be found in the bone. Case presentation We here present a case of metastasis to the scapula in a 54-year-old Caucasian male patient with an advanced gastrointestinal stromal tumor, which was subsequently successfully treated with resection and sunitinib. Conclusion The present study is, to the best of our knowledge, the second to describe scapular metastasis of a gastrointestinal stromal tumor. Our patient was treated by scapulectomy. The overwhelming majority of scapular tumors are metastases that arise from soft tissue, hepatocellular and thyroid tumors. Gastrointestinal stromal tumor metastasis occurs rarely. Scapular surgery can successfully provide local control of the disease. After the surgery, patients should continue with medical treatment.

  15. Neoadjuvant imatinib in locally advanced gastrointestinal stromal tumors

    Directory of Open Access Journals (Sweden)

    Seshadri Ramakrishnan

    2009-01-01

    Full Text Available Aim : To study the role of neoadjuvant imatinib mesylate in downsizing tumors in patients with locally advanced nonmetastatic gastrointestinal stromal tumors (GISTs, thus improving the possibility of complete resection. Materials and Methods : We used neoadjuvant imatinib in six patients with locally advanced GISTs, at a dose of 400 mg daily, given orally in all patients for a median period of 3.5 months (range 1-20 months. All patients had a computerized tomography scan (CT scan once before starting the treatment and a repeat CT scan 1 month after starting imatinib. Some patients had another CT scan done at 3 months. The tumor volume was calculated using the formula V=4/3 πr 3 . Results : Following imatinib therapy, the median reduction in the tumor volume was 40% (range 20-50%. Four of the six patients underwent successful complete resection of the tumor following neoadjuvant imatinib for a median period of 2 months, and are disease free after a median follow-up of 10.5 months (range 3-20 months. Two patients in whom the tumors were deemed to be operable after downsizing refused surgery and are continuing imatinib. Imatinib did not produce serious toxicity in any patient. Conclusion : Neoadjuvant imatinib can be used successfully in patients with locally advanced nonmetastatic GISTs to improve the rates of complete resection and reduce the chance of tumor spill. The optimal duration of neoadjuvant treatment needs to be tailored based on response assessment at frequent intervals to identify the ideal window period for surgery.

  16. Genetics and genomics of ovarian sex cord-stromal tumors.

    Science.gov (United States)

    Fuller, P J; Leung, D; Chu, S

    2017-02-01

    Ovarian sex cord-stromal tumors (SCST) represent approximately 8% of malignant ovarian tumors. The most common are granulosa cell tumors (GCT) which account for approximately 90% of malignant SCST. Recent studies have unraveled the key genomic and genetic events contributing to their pathogenesis. SCST are found in the hereditary syndromes: Peutz-Jeghers syndrome, Ollier disease and Maffucci syndrome, and DICER1 syndrome. Genomic studies have largely been limited to GCT where a number of recurring chromosomal abnormalities (monsomy and trisomy) have been identified although their contribution to pathogenesis remains unclear. In addition to the recurrent DICER1 mutations reported in non-hereditary cases of Sertoli cell and Sertoli-Leydig cell tumors, recurrent somatic mutations in both the juvenile (j) and adult (a) forms of GCT have been reported. Approximately 30% of jGCT contain a somatic mutation, the gsp oncogene, while a further 60% have an activating mutation in the AKT gene. In the case of aGCT, a well characterized mutation in the FOXL2 transcription factor (FOXL2 C134W) is found in almost all cases, which arguably defines the disease, although the molecular events that determine the stage, behavior and prognosis of aGCT remain to be determined. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  17. Phyllodes Tumor of Anogenital Mammary-like Glands with Diffuse Pseudoangiomatous Stromal Hyperplasia

    Directory of Open Access Journals (Sweden)

    Nuket ELİYATKIN

    2017-05-01

    Full Text Available Anogenital mammary-like glands may give rise to various pathologic lesions identical to those known in mammary pathology. Tumor occurring in the anogenital region is extremely rare. The histogenetic origin of this tumor is controversial as it is being debated whether such lesions evolve from ectopic breast tissue and most recently, anogenital mammary-like gland. We report a 28-year-old girl who presented with a painless mass in the anogenital region, which was subsequently excised. Microscopic examination revealed morphologic pattern characteristic of benign phyllodes tumor with pseudoangiomatous stromal hyperplasia. We present this case to emphasize the importance of recognizing this uncommon lesion occurring at an extremely unusual site. We also discuss the histogenesis of phyllodes tumor and related lesions occurring in the anogenital region in light of the current literature along with a brief review of the previously reported cases of anogenital mammary-like glands.

  18. Preoperative imatinib mesylate (IM) for huge gastrointestinal stromal tumors (GIST).

    Science.gov (United States)

    Tang, Sumin; Yin, Yuan; Shen, Chaoyong; Chen, Jiaju; Yin, Xiaonan; Zhang, Bo; Yao, Yuqin; Yang, Jinliang; Chen, Zhixin

    2017-04-11

    Preoperative imatinib mesylate (IM) treatment has not yet been standardized. Here, we aim to further explore such therapy on patients with gastrointestinal stromal tumors (GIST) retrospectively. Patients experiencing preoperative IM were identified from January 2009 to February 2015. A total of 28 GIST patients were identified. The patients received preoperative IM treatment for a median length of 13.5 months, ranging from 5 to 37 months. PR and SD were observed in 24 (85.7%) and 4 (15.3%) patients, respectively. The tumor shrinkage occurred predominantly within 6 to 12 months, and slight tumor shrinkage could be observed after 12 months in certain patients. Nineteen patients (67.9%) received surgery, and R0 resection was acquired in 18 (94.7%) patients. The initial mean maximum diameter was 10.5 (5.2 to 19.0) cm and decreased to 5.9 (2.7 to 19.0) cm after preoperative treatment with a median length of 12 (ranging from 5 to 36) months (P < 0.001) in patients receiving operations. Three in 7 cases of rectum GIST underwent abdominoperineal resection, and four others adopted sphincter-sparing resection. Partial gastrectomy was performed in four patients. IM prior to surgery can effectively prevent tumor rupture and facilitate surgery with low surgical morbidity for GIST patients. Tumor shrinkage following IM occurred predominantly within 6 to 12 months, and slight tumor shrinkage could be observed after 12 months in certain patients. In selected patients, prolonged exposure to IM is seemingly advisable under close radiological surveillance.

  19. Gastrointestinal stromal tumor: a case report and review of the literature

    International Nuclear Information System (INIS)

    Macedo, Leonardo Lopes de; Torres, Lucas Rios; Faucz, Rafael Artigas; Tornin, Olger de Souza; Souza, Ricardo Pires de; Fonseca, Carlos Alberto Marcovechio

    2006-01-01

    Gastrointestinal stromal tumors are the most common mesenchymal tumors and are characterized by expression of KIT (CD117), a tyrosine-kinase growth factor receptor. They occur in individuals over 50 years of age and commonly arise in stomach or in the small intestine. To emphasize our paper we report a case of gastrointestinal stromal tumor that showed the typical image and pathologic findings of the primary lesion and its metastases. (author)

  20. Pheochromocytoma and gastrointestinal stromal tumors in patients with neurofibromatosis type I.

    Science.gov (United States)

    Vlenterie, Myrella; Flucke, Uta; Hofbauer, Lorenz C; Timmers, Henri J L M; Gastmeier, Joerg; Aust, Daniela E; van der Graaf, Winette T A; Wesseling, Pieter; Eisenhofer, Graeme; Lenders, Jacques W M

    2013-02-01

    Neurofibromatosis I may rarely predispose to pheochromocytoma and gastrointestinal stromal tumors. A 59-year-old woman with neurofibromatosis I presented with pheochromocytoma of the left adrenal gland. During surgery, 3 gastrointestinal stromal tumors adjacent to the stomach and small intestine were removed. Despite appropriate thrombosis prophylaxis, the patient died of a pulmonary embolus 2 days postoperatively. The second patient, a 55-year-old man with neurofibromatosis I and bilateral pheochromocytomas, had several small gastrointestinal stromal tumors adjacent to the jejunum during surgery. A review of the literature was conducted to identify patients with neurofibromatosis I with concurrence of pheochromocytoma and gastrointestinal stromal tumors and to define the specific clinical features of these patients. In addition to our 2 patients, 12 other cases of neurofibromatosis I with concomitant occurrence of pheochromocytomas and gastrointestinal stromal tumors have been reported. Pheochromocytomas had adrenal locations in all patients. Two of the 14 patients had a mixed pheochromocytoma/ganglioneuroma. In 4 of the 14 patients, gastrointestinal stromal tumors were located along the stomach. The gastrointestinal stromal tumors in our 2 patients showed no somatic mutations in KIT and PDGFRA genes. A pulmonary embolism was diagnosed in 4 patients. The simultaneous occurrence of pheochromocytoma and gastrointestinal stromal tumor should be considered in all patients with neurofibromatosis I presenting with an abdominal mass with symptoms suggestive of pheochromocytoma. Therefore, a pheochromocytoma should be excluded before a patient with neurofibromatosis I undergoes surgery for a gastrointestinal stromal tumor because an undiagnosed pheochromocytoma carries a high risk of life-threatening cardiovascular complications during surgery. Finally, this combination may be associated with an increased risk for thromboembolic events, but more studies are necessary to

  1. Obscure Gastrointestinal Bleed from a Gastrointestinal Stromal Tumor in a Jejunal Diverticulum: A Rare Case Report

    Directory of Open Access Journals (Sweden)

    A. Sadaf

    2010-01-01

    Full Text Available We present a case of small bowel diverticulum with gastrointestinal stromal tumor (GIST. This GIST in the diverticulum was confirmed by immunohistochemistry and was of low-grade malignant potential.

  2. Small bowel Gastrointestinal Stromal Tumors can physiologically alter gut motility before causing mechanical obstruction

    OpenAIRE

    Kothari, Manish S; Kosmoliaptsis, Vasilis; Meyrick-Thomas, John

    2005-01-01

    Background Gastro Intestinal Stromal Tumors (GISTs) are rare stromal neoplasms that represent the most common mesenchymal tumor of the G.I. tract, accounting for 5% of all sarcomas [1,2]. Originating from interstitial cells of Cajal, which are regulators of gut peristalsis, they are preferentially located in the stomach and the small intestine [3] and clinical presentation is variable, ranging from vague complaints to major G.I. bleeding. Surgical resection is the mainstay of treatment for pa...

  3. Targeting gastrointestinal stromal tumors: the role of regorafenib

    Directory of Open Access Journals (Sweden)

    Schroeder B

    2016-05-01

    Full Text Available Brett Schroeder,1 Zula Li,2,3 Lee D Cranmer,2,3 Robin L Jones,4 Seth M Pollack2,3 1College of Human Medicine, Michigan State University, Grand Rapids, MI, 2Division of Medical Oncology, University of Washington, 3Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; 4Royal Marsden Hospital, Institute of Cancer Research, London, UK Abstract: 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. Keywords: regorafenib, GIST, refractory, imatinib

  4. Interpretation of Pathologic Margin after Endoscopic Resection of Gastrointestinal Stromal Tumor

    OpenAIRE

    Kim, Sang Gyun

    2016-01-01

    Interpretation of the pathologic margin of a specimen from a resected tumor is important because local recurrence can be predicted by the presence of tumor cells in the resection margin. Although a sufficient resection margin is recommended in the resection of gastrointestinal adenocarcinoma, it is not usually regarded strictly in cases of mesenchymal tumor, especially gastrointestinal stromal tumor (GIST), because the tumor is usually encapsulated or well demarcated, and not infiltrative. Th...

  5. Gastrointestinal stromal tumors, somatic mutations and candidate genetic risk variants.

    Directory of Open Access Journals (Sweden)

    Katie M O'Brien

    Full Text Available Gastrointestinal stromal tumors (GISTs are rare but treatable soft tissue sarcomas. Nearly all GISTs have somatic mutations in either the KIT or PDGFRA gene, but there are no known inherited genetic risk factors. We assessed the relationship between KIT/PDGFRA mutations and select deletions or single nucleotide polymorphisms (SNPs in 279 participants from a clinical trial of adjuvant imatinib mesylate. Given previous evidence that certain susceptibility loci and carcinogens are associated with characteristic mutations, or "signatures" in other cancers, we hypothesized that the characteristic somatic mutations in the KIT and PDGFRA genes in GIST tumors may similarly be mutational signatures that are causally linked to specific mutagens or susceptibility loci. As previous epidemiologic studies suggest environmental risk factors such as dioxin and radiation exposure may be linked to sarcomas, we chose 208 variants in 39 candidate genes related to DNA repair and dioxin metabolism or response. We calculated adjusted odds ratios (ORs and 95% confidence intervals (CIs for the association between each variant and 7 categories of tumor mutation using logistic regression. We also evaluated gene-level effects using the sequence kernel association test (SKAT. Although none of the association p-values were statistically significant after adjustment for multiple comparisons, SNPs in CYP1B1 were strongly associated with KIT exon 11 codon 557-8 deletions (OR = 1.9, 95% CI: 1.3-2.9 for rs2855658 and OR = 1.8, 95% CI: 1.2-2.7 for rs1056836 and wild type GISTs (OR = 2.7, 95% CI: 1.5-4.8 for rs1800440 and OR = 0.5, 95% CI: 0.3-0.9 for rs1056836. CYP1B1 was also associated with these mutations categories in the SKAT analysis (p = 0.002 and p = 0.003, respectively. Other potential risk variants included GSTM1, RAD23B and ERCC2. This preliminary analysis of inherited genetic risk factors for GIST offers some clues about the disease's genetic

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

    OpenAIRE

    Sung Jin Oh; Byoung Jo Suh; Jong Kwon Park

    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 a...

  7. Preoperative predictive factors for gastrointestinal stromal tumors: analysis of 375 surgically resected gastric subepithelial tumors.

    Science.gov (United States)

    Min, Yang Won; Park, Ha Na; Min, Byung-Hoon; Choi, Dongil; Kim, Kyoung-Mee; Kim, Sung

    2015-04-01

    Gastrointestinal stromal tumors (GISTs) and non-GIST subepithelial tumors (SETs) account for about 75 and 25% of gastric hypoechoic SETs ≥2 cm, respectively. Therefore, identifying preoperative predictive factors for GISTs are required to refine surgical indications. We performed a retrospective review of 375 surgically resected gastric hypoechoic SETs ≥2 cm. Demographic data and tumor characteristics based on upper endoscopy and CT findings were compared between GIST and non-GIST SETs originating from muscularis propria layer (leiomyomas, Schwannomas, glomus tumors, and ectopic pancreas). In cardia, leiomyomas were found twice more frequently than GISTs (63.6 versus 31.8%). Perilesional lymph node enlargement (PLNE) was found only in patients with GIST or Schwannomas. Patients with GIST showed a significantly lower rate of PLNE than those with Schwannomas (3.5 versus 29.0%). In multivariate analysis, tumor site outside cardia (odds ratio, 9.157), absence of PLNE (odds ratio, 11.519), old age, large tumor size, exophytic growth pattern, and ulceration or dimpling were identified as independent preoperative predictive factors for GISTs versus non-GIST SETs. The effort for preoperative pathologic diagnosis such as endosonography-guided tissue sampling might be positively considered for SETs at cardia and SETs with PLNE where the possibility of GIST is low.

  8. A survey of DICER1 hotspot mutations in ovarian and testicular sex cord-stromal tumors.

    Science.gov (United States)

    Conlon, Niamh; Schultheis, Anne M; Piscuoglio, Salvatore; Silva, Annacarolina; Guerra, Esther; Tornos, Carmen; Reuter, Victor E; Soslow, Robert A; Young, Robert H; Oliva, Esther; Weigelt, Britta

    2015-12-01

    Sertoli-Leydig cell tumors are characterized by the presence of somatic DICER1 hotspot mutations. In this study, we sought to define the association between DICER1 hotspot mutations and different morphologic subtypes of ovarian Sertoli-Leydig cell tumors. Furthermore, we aimed to assess whether DICER1 hotspot mutations occur in other ovarian sex cord-stromal tumors, testicular sex cord-stromal tumors, or other female genital tract tumors with rhabdomyosarcomatous differentiation. We subjected a series of ovarian Sertoli-Leydig cell tumors (n=32), Sertoli cell tumors (n=5) and gynandroblastomas (n=5), testicular sex cord-stromal tumors (n=15) and a diverse group of female genital tract tumors with rhabdomyosarcomatous morphology (n=10) to DICER1 hotspot mutation analysis using Sanger sequencing. We also tested two gynandroblastomas for the presence of FOXL2 hotspot mutations (p.C134W; c.402C>G). Twenty of 32 (63%) Sertoli-Leydig cell tumors harbored a DICER1 hotspot mutation, of which 80% had the p.E1705K mutation. No association was found between DICER1 mutation status and the presence of heterologous or retiform differentiation in Sertoli-Leydig cell tumors. DICER1 mutations were found at similar frequencies in gynandroblastoma (2/5; 40%) and ovarian Sertoli cell tumors (5/8; 63%; P>0.1), and all mutated tumors harbored a p.E1705K mutation. DICER1 hotspot mutations were also identified in a single cervical rhabdomyosarcoma and in the rhabdomyosarcomatous component of a uterine carcinosarcoma. No DICER1 mutations were detected in testicular sex cord-stromal tumors. Two DICER1 wild-type gynandroblastomas harbored a p.C134W FOXL2 hotspot mutation in both tumor components. In this study we confirmed that DICER1 hotspot mutations occur in over half of ovarian Sertoli-Leydig cell tumors, and are unrelated to tumor differentiation. We also widened the spectrum of ovarian sex cord-stromal tumors with sertoliform differentiation, in which DICER1 mutations are known to

  9. Management of a Gastrobronchial Fistula Connected to the Skin in a Giant Extragastric Stromal Tumor

    Directory of Open Access Journals (Sweden)

    Emilio Muñoz

    2015-01-01

    Full Text Available Introduction. Gastrointestinal stromal tumors first treatment should be surgical resection, but when metastases are diagnosed or the tumor is unresectable, imatinib must be the first option. This treatment could induce some serious complications difficult to resolve. Case Report. We present a 47-year-old black man with a giant unresectable gastric stromal tumor under imatinib therapy who presented serious complications such as massive gastrointestinal bleeding and a gastrobronchial fistula connected with the skin, successfully treated by surgery and gastroscopy. Discussion. Complications due to imatinib therapy can result in life threatening. They represent a challenge for surgeons and digestologists; creative strategies are needed in order to resolve them.

  10. Imaging of Gastrointestinal Stromal Tumors before and after Imatinib Mesylate Therapy

    Energy Technology Data Exchange (ETDEWEB)

    Shankar, S.; Dundamadappa, S.K.; Karam, A.R. (Radiology Dept., Univ. of Massachusetts Medical Center, Worcester, MA (United States)); Stay, R.M. (Radiology Dept., Univ. of Virginia, Charlottesville, VA (United States)); Sonnenberg, E. van (Radiology Dept., Dana Farber Cancer Inst., Boston, MA (United States))

    2009-10-15

    Gastrointestinal stromal tumors (GISTs) account for the majority of gastrointestinal mesenchymal tumors. Recent advances in treatment using the molecular targeting agent imatinib mesylate have shown startling response rates and variegated imaging findings. We present the various imaging appearances of GIST on computed tomography (CT) and magnetic resonance imaging (MRI), both before and after treatment.

  11. Giant gastrointestinal stromal tumor of the vermiform appendix: A case report.

    Science.gov (United States)

    Kaneko, Manabu; Kawai, Kazushige; Murono, Koji; Nishikawa, Takeshi; Sasaki, Kazuhito; Otani, Kensuke; Yasuda, Koji; Tanaka, Toshiaki; Kiyomatsu, Tomomichi; Hata, Keisuke; Nozawa, Hiroaki; Ishihara, Soichiro; Hayashi, Akimasa; Shinozaki-Ushiku, Aya; Fukayama, Masashi; Watanabe, Toshiaki

    2017-09-01

    Gastrointestinal stromal tumors (GISTs) of the vermiform appendix are rare, measuring vermiform appendix, and that the peritoneal metastasis was located in the ascending mesocolon. The patient underwent laparoscopic appendectomy and excision of the peritoneal metastasis, without tumor rupture. Therefore, in appropriately selected patients, neoadjuvant imatinib for borderline resectable or oligometastatic GISTs may be a reasonable choice.

  12. Collagen reorganization at the tumor-stromal interface facilitates local invasion

    Directory of Open Access Journals (Sweden)

    Inman David R

    2006-12-01

    Full Text Available Abstract Background Stromal-epithelial interactions are of particular significance in breast tissue as misregulation of these interactions can promote tumorigenesis and invasion. Moreover, collagen-dense breast tissue increases the risk of breast carcinoma, although the relationship between collagen density and tumorigenesis is not well understood. As little is known about epithelial-stromal interactions in vivo, it is necessary to visualize the stroma surrounding normal epithelium and mammary tumors in intact tissues to better understand how matrix organization, density, and composition affect tumor formation and progression. Methods Epithelial-stromal interactions in normal mammary glands, mammary tumors, and tumor explants in three-dimensional culture were studied with histology, electron microscopy, and nonlinear optical imaging methodologies. Imaging of the tumor-stromal interface in live tumor tissue ex vivo was performed with multiphoton laser-scanning microscopy (MPLSM to generate multiphoton excitation (MPE of endogenous fluorophores and second harmonic generation (SHG to image stromal collagen. Results We used both laser-scanning multiphoton and second harmonic generation microscopy to determine the organization of specific collagen structures around ducts and tumors in intact, unfixed and unsectioned mammary glands. Local alterations in collagen density were clearly seen, allowing us to obtain three-dimensional information regarding the organization of the mammary stroma, such as radiating collagen fibers that could not have been obtained using classical histological techniques. Moreover, we observed and defined three tumor-associated collagen signatures (TACS that provide novel markers to locate and characterize tumors. In particular, local cell invasion was found predominantly to be oriented along certain aligned collagen fibers, suggesting that radial alignment of collagen fibers relative to tumors facilitates invasion. Consistent

  13. Epidemiology, survival, and costs of localized gastrointestinal stromal tumors

    Directory of Open Access Journals (Sweden)

    Jaime L Rubin

    2011-02-01

    Full Text Available Jaime L Rubin1, Myrlene Sanon1, Douglas CA Taylor1, John Coombs2, Vamsi Bollu2, Leonardo Sirulnik21i3 Innovus, Medford, MA, USA; 2Novartis Pharmaceuticals, East Hanover, NJ, USAPurpose: The aim of this study is to examine the epidemiologic and economic burden in surgically resected localized gastrointestinal stromal tumor (GIST patients versus age- and gender-matched controls.Method: Two data sources were used to conduct a series of complementary analyses. First, the Surveillance, Epidemiology, and End Results (SEER cancer registry was used to identify diagnosed GIST patients from 1993 to 2002 and determine incidence, prevalence, and 3-year survival. Second, using the SEER–Medicare linked database, a matched case-control analysis was conducted to determine resource utilization, GIST recurrence, and costs. Because GIST recurrence is not explicitly defined in the database, patterns in resource use were used to identify probable recurrence. Kaplan–Meier Sample Average (KMSA Estimator technique was used to estimate costs of GIST and recurrence.Results: SEER registry results show over the 10-year time horizon average annual GIST incidence was 0.32 per 100,000 persons in the United States, 15-year limited-duration prevalence was 1.62 per 100,000 persons, and 3-year survival was 73%. A total of 292 GIST patients were included in the SEER–Medicare analyses; 35 were identified with probable recurrence. GIST patients had increased risk of mortality (hazard ratio: 1.23; 95% confidence intervals: 0.94–1.61 compared to controls. Median recurrence-free and postrecurrence survival was 45 and 46 months, respectively. GIST patients incurred significantly higher medical care costs in the first year after initial resection, with $23,221 attributable to GIST. GIST recurrence costs totaled $101,700 over 5 years after initial resection.Conclusions: GIST is associated with substantial medical care costs, estimated recurrence costs more than $100

  14. Gastrointestinal stromal tumors arising from the stomach: a report of three children.

    Science.gov (United States)

    Durham, Megan M; Gow, Kenneth W; Shehata, Bahig M; Katzenstein, Howard M; Lorenzo, Robert L; Ricketts, Richard R

    2004-10-01

    Gastrointestinal stromal tumors (GIST) are a unique subset of intestinal mesenchymal tumors that behave in an aggressive fashion. They have been commonly described in adults but have been rarely observed in children. The authors review the presentation, diagnostic workup, operative records, pathologic specimens, and outcomes of 3 children with GISTs that originated from the stomach. All 3 children presented after upper gastrointestinal bleeding from the gastric tumor. The first was a 10-year-old girl who underwent partial gastrectomy but had recurrence 8 years later requiring a second resection. She subsequently had a hepatic metastasis 8 years later requiring a third resection. The second patient was a 9-year-old girl who had an antrectomy with a Bilroth I reconstruction and was noted to have a synchronous liver metastasis that was also resected. Despite Imatinib Mesylate, she had further hepatic metastases. The third child was a 4-year-old boy who recently underwent a partial gastrectomy and has no signs of metastatic disease at this time. GISTs are unusual tumors that have been rarely described in children. When they arise in the stomach, they often present after upper gastrointestinal bleeding. Diagnosis can be made by endoscopy and biopsy. GISTs require resection and close observation for hepatic metastases. Current studies are ongoing for the potential role of Imatinib Mesylate for GISTs in children.

  15. Aspects of surgical treatment for gastro-intestinal stromal tumors; Chirurgische Therapieaspekte gastrointestinaler Stromatumoren

    Energy Technology Data Exchange (ETDEWEB)

    Hohenberger, P. [Medizinische Fakultaet Mannheim, Universitaet Heidelberg, Sektion Chirurgische Onkologie und Thoraxchirurgie, Chirurgische Universitaetsklinik, Mannheim (Germany)

    2009-12-15

    Gastro-intestinal stromal tumors (GIST) form the commonest subgroup of soft tissue sarcomas. They arise in the muscular layer of the esophagus, stomach, small intestines and rectum. Characteristic and important for the assessment of the extent of tumors is the peripheral rim vascularization of primary tumors and metastases. Indications for resection are given for tumors larger than 2 cm in size. Locally advanced GISTs can be advantageously treated with imatinib/sunitinib as neoadjuvant and it is often possible to select a low level of resection for this size of tumor and when the rim area is not hypervascularized. Even in the metastizing stage surgical treatment can be used for elimination of resistant metastases or for removal of residual tumor tissue in an attempt to counteract secondary tumor progression. The effect of this treatment is currently being tested in a randomized phase III study. (orig.) [German] Gastrointestinale Stromatumoren (GIST) stellen die haeufigste Subgruppe von Weichgewebesarkomen dar. Sie entstehen in der Muskularisschicht von Oesophagus, Magen, Duenndarm und Rektum. Charakteristisch und wichtig fuer die Einschaetzung des Tumorausmasses ist die Randvaskularisation von Primaertumoren und Metastasen. Die Indikation zur Resektion gilt fuer Tumoren ab 2 cm Groesse. Lokal fortgeschrittene GIST koennen sehr vorteilhaft mit Imatinib/Sunitinib neoadjuvant vorbehandelt werden, und es ist oft moeglich, bei der Tumorgroesse und wenn keine hypervaskularisierten Randbereiche vorliegen, ein geringeres Resektionsausmass zu waehlen. Auch im metastasierten Stadium hat die chirurgische Therapie einen Platz zur Eliminierung resistenter Metastasen bzw. zur Entfernung von Residualtumorgewebe als Versuch, einer sekundaeren Tumorprogression zu begegnen. Dieser Behandlungseffekt wird derzeit in einer randomisierten Phase-III-Studie ueberprueft. (orig.)

  16. Small submucosal tumors of the stomach: differentiation of gastric schwannoma from gastrointestinal stromal tumor with CT.

    Science.gov (United States)

    Choi, Jin Wook; Choi, Dongil; Kim, Kyoung-Mee; Sohn, Tae Sung; Lee, Jun Haeng; Kim, Hee Jung; Lee, Soon Jin

    2012-01-01

    To identify the CT features that help differentiate gastric schwannomas (GS) from small (5 cm or smaller) gastrointestinal stromal tumors (GIST) and to assess the growth rates of both tumors. We included 16 small GSs and 56 GISTs located in the stomach. We evaluated the CT features including size, contour, surface pattern, margins, growth pattern, pattern and degree of contrast enhancement, and the presence of intralesional low attenuation area, hemorrhage, calcification, surface dimpling, fistula, perilesional lymph nodes (LNs), invasion to other organs, metastasis, ascites, and peritoneal seeding. We also estimated the tumor volume doubling time. Compared with GISTs, GSs more frequently demonstrated a homogeneous enhancement pattern, exophytic or mixed growth pattern, and the presence of perilesional LNs (each p < 0.05). The intralesional low attenuation area was more common in GISTs than GSs (p < 0.05). Multivariate analyses indicated that a homogeneous enhancement pattern, exophytic or mixed growth pattern, and the presence of perilesional LNs were statistically significant (p < 0.05). Tumor volume doubling times for GSs (mean, 1685.4 days) were significantly longer than that of GISTs (mean, 377.6 days) (p = 0.004). Although small GSs and GISTs show similar imaging findings, GSs more frequently show an exophytic or mixed growth pattern, homogeneous enhancement pattern, perilesional LNs and grow slower than GISTs.

  17. Small Submucosal Tumors of the Stomach: Differentiation of Gastric Schwannoma from Gastrointestinal Stromal Tumor with CT

    Energy Technology Data Exchange (ETDEWEB)

    Choi, Jin Wook; Choi, Dong Gil; Kim, Kyoung Mee; Sohn, Tae Sung; Lee, Jun Haeng; Kim, Hee Jung; Lee, Soon Jin [Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul (Korea, Republic of)

    2012-07-15

    To identify the CT features that help differentiate gastric schwannomas (GS) from small (5 cm or smaller) gastrointestinal stromal tumors (GIST) and to assess the growth rates of both tumors. We included 16 small GSs and 56 GISTs located in the stomach. We evaluated the CT features including size, contour, surface pattern, margins, growth pattern, pattern and degree of contrast enhancement, and the presence of intralesional low attenuation area, hemorrhage, calcification, surface dimpling, fistula, perilesional lymph nodes (LNs), invasion to other organs, metastasis, ascites, and peritoneal seeding. We also estimated the tumor volume doubling time. Compared with GISTs, GSs more frequently demonstrated a homogeneous enhancement pattern, exophytic or mixed growth pattern, and the presence of perilesional LNs (each p < 0.05). The intralesional low attenuation area was more common in GISTs than GSs (p < 0.05). Multivariate analyses indicated that a homogeneous enhancement pattern, exophytic or mixed growth pattern, and the presence of perilesional LNs were statistically significant (p < 0.05). Tumor volume doubling times for GSs (mean, 1685.4 days) were significantly longer than that of GISTs (mean, 377.6 days) (p = 0.004). Although small GSs and GISTs show similar imaging findings, GSs more frequently show an exophytic or mixed growth pattern, homogeneous enhancement pattern, perilesional LNs and grow slower than GISTs.

  18. Intranodal Schwannoma Mimicking a Gastrointestinal Stromal Tumor of the Stomach: A Case Report

    Energy Technology Data Exchange (ETDEWEB)

    Nam, Kyung Bum; Namkyoung, Sook; Kim, Heung Cheol [Dept. of Radiology, Chuncheon Scared Heart Hospital, Hallym University College of Medicine, Chuncheon (Korea, Republic of); Kim, Hae Sung; Ryu, Byoung Yoon [Dept. of General Surgery, Chuncheon Scared Heart Hospital, Hallym University College of Medicine, Chuncheon (Korea, Republic of); Cha, Young Hee [Dept. of Pathology, Chuncheon Scared Heart Hospital, Hallym University College of Medicine, Chuncheon (Korea, Republic of)

    2011-10-15

    A 66-year-old-woman is presented with intranodal schwannoma of the retroperitoneum. Ultrasonography (US) and computed tomography (CT) results demonstrated a large encapsulated mass with internal cystic or necrotic portions in the gastrosplenic space. The tumor abutted the greater curvature of the gastric body and slightly indented the proximal small bowel loops on a small bowel series. The observations suggested a gastrointestinal stromal tumor. The mass was surgically proven to be a retroperitoneal tumor and histopathologically intranodal ancient schwannoma.

  19. A Rare Case of Mesenteric Gastrointestinal Stromal Tumor ...

    African Journals Online (AJOL)

    Gastrointestinal stromal tumours (GIST) are rare tumours arising from mesenchyme of gastrointestinal tract and overexpress C-kit protein. Mainly seen in stomach and small bowel. Mesenteric GIST are rarely reported as they constitute less than 1% of total GIST. We here report such a rare case of GIST arising from ...

  20. Glucose Promotes a Pro-Oxidant and Pro-Inflammatory Stromal Microenvironment Which Favors Motile Properties in Breast Tumor Cells.

    Science.gov (United States)

    Kallens, Violeta; Tobar, Nicolás; Molina, Jessica; Bidegain, Arantzazú; Smith, Patricio C; Porras, Omar; Martínez, Jorge

    2017-05-01

    Chronic inflammation and metabolic reprogramming have been proposed as hallmarks of cancer development. Currently, many of the functional clues between these two phenomena are studied under the integrative view of functional stroma-epithelia interaction. It has been proposed that stromal cells, due to their abundance and avidity for glucose, are able to modify the metabolic behavior of an entire solid tumor. In the present study, using a mammary stromal cell line derived from healthy tissue subjected to long-term culture in low (5 mM) or high (25 mM) glucose, we found that the hyperglycemic condition favors the establishment of a pro-inflammatory and pro-oxidant environment characterized by the induction of the COX-2/PGE2 axis. In this condition, epithelial migration was stimulated. Moreover, we also found that stromal-derived PGE2, acting as a stimulator of IL-1 epithelial expression was one of the factors that promote the acquisition of motile properties by epithelial cells and the maintenance of a COX-2/PGE2-dependent inflammatory condition. Overall, our work provides experimental evidence that glucose stimulates a tumor inflammatory environment that, as a result of a functional cross-talk between stroma and epithelia, may be responsible for tumor progression. J. Cell. Biochem. 118: 994-1002, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  1. Tumor and Stromal-Based Contributions to Head and Neck Squamous Cell Carcinoma Invasion

    Energy Technology Data Exchange (ETDEWEB)

    Markwell, Steven M.; Weed, Scott A., E-mail: scweed@hsc.wvu.edu [Department of Neurobiology and Anatomy, Program in Cancer Cell Biology, Mary Babb Randolph Cancer Center, West Virginia University, Morgantown, WV 26506 (United States)

    2015-02-27

    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.

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

    Directory of Open Access Journals (Sweden)

    Giuseppe Merlino

    2016-05-01

    Full Text Available 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.

  3. Prostatic stromal tumor with fatal outcome in a young man: histopathological and immunohistochemical case presentation

    Directory of Open Access Journals (Sweden)

    Massimo Roncalli

    2010-12-01

    Full Text Available Stromal tumors of the prostate are rare and only a few cases have been described in the literature, including exceptional cases of stromal tumors with unknown malignant potential (STUMP and a fatal outcome in young patients. Morphologically distinguishing a STUMP from a stromal sarcoma of the prostate (PSS is still a challenge. We describe the histopathological and immunohistochemical findings in a 34-year-old man with a malignant specialized cell stromal tumor of the prostate that was diagnosed initially as STUMP, and he developed lung metastases within a few months. The patient attended our hospital because of lower urinary tract symptoms, after having excreted tissue through the urethra a few months before. Ultrasonography and urethrocystoscopy examinations showed a mass arising from the verumontanum, and a transurethral resection (TUR revealed a high-grade spindle cell sarcoma reminiscent of a phyllode tumor of the breast. The tumor cells were immunoreactive for vimentin, progesterone receptor and, focally, CD34. The preliminary histo­logical findings were subsequently confirmed after radical prostatectomy. The patient developed bilateral lung metastases and died 25 months after the initial diagnosis. Although rare in young patients, the challenging differential diagnosis of STUMP and PSS means that a prostate STUMP diagnosis made on the basis of biopsy or TUR specimens also requires urethrocystoscopic monitoring for the early detection of any progression to PSS. Radical prostatectomy should also be carefully considered.

  4. FGFR1 and NTRK3 actionable alterations in ?Wild-Type? gastrointestinal stromal tumors

    OpenAIRE

    Shi, Eileen; Chmielecki, Juliann; Tang, Chih-Min; Wang, Kai; Heinrich, Michael C.; Kang, Guhyun; Corless, Christopher L.; Hong, David; Fero, Katherine E.; Murphy, James D.; Fanta, Paul T.; Ali, Siraj M.; De Siena, Martina; Burgoyne, Adam M.; Movva, Sujana

    2016-01-01

    Background About 10?15% of adult, and most pediatric, gastrointestinal stromal tumors (GIST) lack mutations in KIT, PDGFRA, SDHx, or RAS pathway components (KRAS, BRAF, NF1). The identification of additional mutated genes in this rare subset of tumors can have important clinical benefit to identify altered biological pathways and select targeted therapies. Methods We performed comprehensive genomic profiling (CGP) for coding regions in more than 300 cancer-related genes of 186 GISTs to assess...

  5. Alerting the immune system via stromal cells is central to the prevention of tumor growth

    DEFF Research Database (Denmark)

    Navikas, Shohreh

    2013-01-01

    Anticancer immunotherapies are highly desired. Conversely, unwanted inflammatory or immune responses contribute to oncogenesis, tumor progression, and cancer-related death. For non-immunogenic therapies to inhibit tumor growth, they must promote, not prevent, the activation of anticancer immune...... responses. Here, the central immunoregulatory role of brain-specific stromal cells and neurons as well as their ability to maintain an immunological balance and prevent the development of glioblastoma is discussed....

  6. Loss of stromal caveolin-1 expression: a novel tumor microenvironment biomarker that can predict poor clinical outcomes for pancreatic cancer.

    Directory of Open Access Journals (Sweden)

    Tao Shan

    Full Text Available 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.

  7. An Intra-Abdominal Desmoid Tumor, Embedded in the Pancreas, Preoperatively Diagnosed as an Extragastric Growing Gastrointestinal Stromal Tumor

    Directory of Open Access Journals (Sweden)

    Mari Mizuno

    2017-04-01

    Full Text Available A 45-year-old woman was found to have a pancreatic tumor by abdominal ultrasound performed for a medical check-up. Abdominal contrast-enhanced computed tomography showed a hypovascular tumor measuring 30 mm in diameter in the pancreatic tail. Endoscopic ultrasound-guided fine needle aspiration was performed. An extragastric growing gastrointestinal stromal tumor was thereby diagnosed preoperatively, and surgical resection was planned. Laparoscopic surgery was attempted but conversion to open surgery was necessitated by extensive adhesions, and distal pancreatectomy, splenectomy, and partial gastrectomy were performed. The histological diagnosis was an intra-abdominal desmoid tumor. A desmoid tumor is a fibrous soft tissue tumor arising in the fascia and musculoaponeurotic tissues. It usually occurs in the extremities and abdominal wall, and only rarely in the abdominal cavity. We experienced a case with an intra-abdominal desmoid tumor that was histologically diagnosed after laparotomy, which had been preoperatively diagnosed as an extragastric growing gastrointestinal stromal tumor. Although rare, desmoid tumors should be considered in the differential diagnosis of intra-abdominal tumors. Herein, we report this case with a literature review.

  8. Extra-Gastrointestinal Stromal Tumor Presenting as an Anterior Chest Wall Mass

    Directory of Open Access Journals (Sweden)

    Junghyeon Lim

    2017-08-01

    Full Text Available A 71-year-old man was referred for an anterior chest wall mass. Chest computed tomography (CT and positron emission tomography-CT suggested a malignant tumor. Surgical biopsy through a vertical subxiphoid incision revealed an extra-gastrointestinal stromal tumor (EGIST. En bloc resection of the tumor, including partial resection of the sternum, costal cartilage, pericardium, diaphragm, and peritoneum, was performed. Pathologic evaluation revealed a negative resection margin and confirmed the tumor as an EGIST. On postoperative day 17, the patient was discharged without any complications. At the 2-week follow-up, the patient was doing well and was asymptomatic.

  9. Tumoral pseudoangiomatous stromal hyperplasia: Radiological and pathological correlation with review of literature

    Directory of Open Access Journals (Sweden)

    Noora Rafeek

    2017-03-01

    Full Text Available Tumoral pseudoangiomatous stromal hyperplasia (PASH is rare and presents more often as a clinically apparent, well-circumscribed, solid mass. It may clinically and radiologically mimic fibroadenoma or Phyllodes tumor. In this article, our objective was to describe the clinical presentations, ultrasound and histopathological appearances of tumoral PASH in three patients. Among the three PASH tumors, all except one were palpable breast masses; and the non-palpable mass was detected on ultrasound. All patients underwent core biopsy followed by wide local excision of the mass which were histopathologically proven to be PASH.

  10. Therapy-activated stromal cells can dictate tumor fate

    OpenAIRE

    Kerbel, Robert S.; Shaked, Yuval

    2016-01-01

    In this issue of JEM, Chan et al. describe a novel way by which an investigational form of chemotherapy known as low-dose metronomic chemotherapy can inhibit tumor growth, which also has therapeutic implications for targeting tumor-initiating cells (TICs), the tumor stroma, and chemokine receptors, as well as invasion and metastasis.

  11. Numerical modelling of the influence of stromal cells on tumor growth and angiogenesis

    Science.gov (United States)

    Sakiyama, Nobuyuki; Nagayama, Katsuya

    2018-01-01

    According to the statistics provided by the Ministry of Health, Labor and Welfare the death of one in 3.5 Japanese people is attributed to tumor highlighting the need for active research on malignant tumors. Early detection can be cited as a countermeasure against malignant tumors, but it is often difficult to observe the growth process, and thorough understanding of the phenomena will aid in more efficient detection of such tumors. A malnourished benign tumor may create new blood vessels from existing ones and proliferate abnormally by absorbing nutrients from these newly created blood vessels to become malignant. Different factors influence the shape of tumors and shape is an important factor in evaluating their malignancy. Because interstitial cells greatly influence tumor growth, investigating the influence of stromal cells on tumor growth will help in developing a better understanding of the phenomenon.

  12. The Inside Mystery of Jejunal Gastrointestinal Stromal Tumor: A Rare Case Report and Review of the Literature

    OpenAIRE

    Dhull, A. K.; Kaushal, V.; Dhankhar, R.; Atri, R.; Singh, H.; Marwah, N.

    2011-01-01

    Gastrointestinal stromal tumors (GISTs) are malignant and rare form of soft tissue sarcoma of the digestive tract. The incidence of gastrointestinal stromal tumors is very low Kramer et al. 2005 Jejunal GISTs are extremely rare. Here we present a rare case of jejunal GIST with unusually large size at presentation. The patient presented with severe abdomen pain, exophytic growth, and dimorphic anemia. Surgical resection of the tumor was carried out, and operative findings revealed a 15 × 10 cm...

  13. Tumor stromal vascular endothelial growth factor A is predictive of poor outcome in inflammatory breast cancer

    International Nuclear Information System (INIS)

    Arias-Pulido, Hugo; Chaher, Nabila; Gong, Yun; Qualls, Clifford; Vargas, Jake; Royce, Melanie

    2012-01-01

    Inflammatory breast cancer (IBC) is a highly angiogenic disease; thus, antiangiogenic therapy should result in a clinical response. However, clinical trials have demonstrated only modest responses, and the reasons for these outcomes remain unknown. Therefore, the purpose of this retrospective study was to determine the prognostic value of protein levels of vascular endothelial growth factor (VEGF-A), one of the main targets of antiangiogenic therapy, and its receptors (VEGF-R1 and -R2) in IBC tumor specimens. Specimens from IBC and normal breast tissues were obtained from Algerian patients. Tumor epithelial and stromal staining of VEGF-A, VEGF-R1, and VEGF-R2 was evaluated by immunohistochemical analysis in tumors and normal breast tissues; this expression was correlated with clinicopathological variables and breast cancer-specific survival (BCSS) and disease-free survival (DFS) duration. From a set of 117 IBC samples, we evaluated 103 ductal IBC tissues and 25 normal specimens. Significantly lower epithelial VEGF-A immunostaining was found in IBC tumor cells than in normal breast tissues (P <0.01), cytoplasmic VEGF-R1 and nuclear VEGF-R2 levels were slightly higher, and cytoplasmic VEGF-R2 levels were significantly higher (P = 0.04). Sixty-two percent of IBC tumors had high stromal VEGF-A expression. In univariate analysis, stromal VEGF-A levels predicted BCSS and DFS in IBC patients with estrogen receptor-positive (P <0.01 for both), progesterone receptor-positive (P = 0.04 and P = 0.03), HER2+ (P = 0.04 and P = 0.03), and lymph node involvement (P <0.01 for both). Strikingly, in a multivariate analysis, tumor stromal VEGF-A was identified as an independent predictor of poor BCSS (hazard ratio [HR]: 5.0; 95% CI: 2.0-12.3; P <0.01) and DFS (HR: 4.2; 95% CI: 1.7-10.3; P <0.01). To our knowledge, this is the first study to demonstrate that tumor stromal VEGF-A expression is a valuable prognostic indicator of BCSS and DFS at diagnosis and can therefore be used to

  14. A mouse model of luciferase-transfected stromal cells of giant cell tumor of bone.

    Science.gov (United States)

    Lau, Carol P Y; Wong, Kwok Chuen; Huang, Lin; Li, Gang; Tsui, Stephen K W; Kumta, Shekhar Madhukar

    2015-11-01

    A major barrier towards the study of the effects of drugs on Giant Cell Tumor of Bone (GCT) has been the lack of an animal model. In this study, we created an animal model in which GCT stromal cells survived and functioned as proliferating neoplastic cells. A proliferative cell line of GCT stromal cells was used to create a stable and luciferase-transduced cell line, Luc-G33. The cell line was characterized and was found that there were no significant differences on cell proliferation rate and recruitment of monocytes when compared with the wild type GCT stromal cells. We delivered the Luc-G33 cells either subcutaneously on the back or to the tibiae of the nude mice. The presence of viable Luc-G33 cells was assessed using real-time live imaging by the IVIS 200 bioluminescent imaging (BLI) system. The tumor cells initially propagated and remained viable on site for 7 weeks in the subcutaneous tumor model. We also tested in vivo antitumor effects of Zoledronate (ZOL) and Geranylgeranyl transferase-I inhibitor (GGTI-298) alone or their combinations in Luc-G33-transplanted nude mice. ZOL alone at 400 µg/kg and the co-treatment of ZOL at 400 µg/kg and GGTI-298 at 1.16 mg/kg reduced tumor cell viability in the model. Furthermore, the anti-tumor effects by ZOL, GGTI-298 and the co-treatment in subcutaneous tumor model were also confirmed by immunohistochemical (IHC) staining. In conclusion, we established a nude mice model of GCT stromal cells which allows non-invasive, real-time assessments of tumor development and testing the in vivo effects of different adjuvants for treating GCT.

  15. The safety of regorafenib for the treatment of gastrointestinal stromal tumors.

    Science.gov (United States)

    Rutkowski, Piotr; Stępniak, Joanna

    2016-01-01

    The management of gastrointestinal stromal tumors (GIST) evolved due to effective molecularly targeted therapy with imatinib and sunitinib which are used first- and second-line, respectively. However, due to the development of resistance to those drugs in the majority of patients, the need for third-line therapy arose. Regorafenib, an oral multitargeted inhibitor with activity against multiple kinases including KIT, RET, RAF1, BRAF, angiogenesis (VEGFR, TIE-2) and those involved in tumor microenvironment (PDGFR and FGFR) was introduced after the successful Phase III GRID (GIST - Regorafenib In progressive Disease) clinical trial. This study showed significant improvement in progression-free survival for patients receiving regorafenib compared to placebo (4.8 months vs 0.9 months). The treatment was reasonably well tolerated, with arterial hypertension, hand-foot syndrome, diarrhea being the most common grade ≥3 adverse events, which could be managed by dose reduction and supportive treatment. The aim of this paper is to describe, assess and advise on the safety of regorafenib as third-line therapy in GIST. Regorafenib has demonstrated clinical benefit in GIST patients after progression on prior treatment with at least imatinib/sunitinib and currently it is the approved standard third-line option in therapy of advanced GIST. The safety profile is similar to other multikinase inhibitors with anti-VEGFR activity and is manageable.

  16. Pfetin as a Risk Factor of Recurrence in Gastrointestinal Stromal Tumors

    Directory of Open Access Journals (Sweden)

    Hajime Orita

    2014-01-01

    Full Text Available Background. Despite complete resection of gastrointestinal stromal tumors (GIST, recurrent and/or metastatic disease occurs, often depending on the grade of malignancy. As such, markers are needed that accurately predict patients at high risk for recurrence. Previously our group reported Pfetin as a prognostic biomarker for GIST. In order to create an approach for predicting risk of recurrence, we incorporated Pfetin expression with clinicopathological data to produce a predictive model. Object. Forty-five patients with localized primary GIST were treated with complete gross surgical resection surgically at our institution between 1995 and 2010 were included. The majority of tumors originated in the stomach (38 cases, as well as small intestine (6 cases and rectum (1 case. Method. (1 We performed retrospective analysis of the connection between Pfetin expression, clinicopathological data, and incidences of recurrence, using bivariate and multivariate analyses. (2 The reactivity of the monoclonal antibody against Pfetin was examined by immunohistochemistry. Pfetin. We have reported Pfetin, identified microarray technology, and compared between statistically different GISTs for good and poor prognoses and for prognostic marker. Results. There were 7 cases of recurrences. (1 By univariate analysis, tumor size, mitoses, exposure to abdominal cavity, and complete tumor removal predicted risk of recurrence. (2 Pfetin-negative cases were significantly related to recurrence (P = 0.002. Conclusions. This analysis demonstrates that lack of Pfetin expression is an additional predictor of recurrence in resected GIST. Further study may determine the role of this variable added to the current predictive model for selection of adjuvant therapy.

  17. Incidental detection of gastrointestinal stromal tumor by Tc-99m MDP bone scan.

    Science.gov (United States)

    Shepherd, Timothy M; Idakoji, Ibrahim A; Pampaloni, Miguel H

    2012-02-01

    This case demonstrates extraosseous 99m-technetium methylene diphosphonate (Tc-99m MDP) accumulation from a gastrointestinal stromal tumor. A 75-year-old woman underwent a temporal bone CT for conductive hearing loss that showed sclerosis in the right occipital condyle. Follow-up Tc-99m MDP bone scan for osseous metastases instead showed a mass-like extraosseous accumulation of Tc-99m MDP in the anterior left upper quadrant. Differential diagnoses included gastric cancer, lymphoma, metastatic melanoma, systemic hypercalcemia, or heterotopic mesenteric ossification. Contrast CT showed a well-circumscribed mass arising from the stomach, and subsequent pathology confirmed gastrointestinal stromal tumor. These tumors rarely can contain osteoclast-like giant cells and should be considered for extraosseous Tc-99m MDP accumulation.

  18. Interpretation of Pathologic Margin after Endoscopic Resection of Gastrointestinal Stromal Tumor

    Science.gov (United States)

    Kim, Sang Gyun

    2016-01-01

    Interpretation of the pathologic margin of a specimen from a resected tumor is important because local recurrence can be predicted by the presence of tumor cells in the resection margin. Although a sufficient resection margin is recommended in the resection of gastrointestinal adenocarcinoma, it is not usually regarded strictly in cases of mesenchymal tumor, especially gastrointestinal stromal tumor (GIST), because the tumor is usually encapsulated or well demarcated, and not infiltrative. Therefore, margin positivity is not rare in the pathological evaluation of surgically or endoscopically resected GIST, and does not always indicate incomplete resection. Although a GIST may have a tumor-positive pathologic margin, complete resection may be achieved if no residual tumor is visible, and long-term survival can be predicted as in the cases with a negative pathologic margin. PMID:27055454

  19. T cells stimulate catabolic gene expression by the stromal cells from giant cell tumor of bone

    Energy Technology Data Exchange (ETDEWEB)

    Cowan, Robert W. [Department of Pathology and Molecular Medicine, McMaster University, 1280 Main St. W., Hamilton, ON, Canada L8S 4L8 (Canada); Juravinski Cancer Centre, 699 Concession St., Hamilton, ON, Canada L8V 5C2 (Canada); Ghert, Michelle [Juravinski Cancer Centre, 699 Concession St., Hamilton, ON, Canada L8V 5C2 (Canada); Department of Surgery, McMaster University, 1280 Main St. W., Hamilton, ON, Canada L8S 4L8 (Canada); Singh, Gurmit, E-mail: gurmit.singh@jcc.hhsc.ca [Department of Pathology and Molecular Medicine, McMaster University, 1280 Main St. W., Hamilton, ON, Canada L8S 4L8 (Canada); Juravinski Cancer Centre, 699 Concession St., Hamilton, ON, Canada L8V 5C2 (Canada)

    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

  20. Stromal Cells and Integrins: Conforming to the Needs of the Tumor Microenvironment

    Directory of Open Access Journals (Sweden)

    Aimee Alphonso

    2009-12-01

    Full Text Available The microenvironment of a tumor is constituted of a heterogenous population of stromal cells, extracellular matrix components, and secreted factors, all of which make the tumor microenvironment distinct from that of normal tissue. Unlike healthy cells, tumor cells require these unique surroundings to metastasize, spread, and form a secondary tumor at a distant site. In this review, we discuss that stromal cells such as fibroblasts and immune cells including macrophages, their secreted factors, such as vascular endothelial growth factor, transforming growth factor β, and various chemokines, and the integrins that connect the various cell types play a particularly vital role in the survival of a growing tumor mass. Macrophages and fibroblasts are uniquely plastic cells because they are not only able to switch from tumor suppressing to tumor supporting phenotypes but also able to adopt various tumor-supporting functions based on their location within the microenvironment. Integrins serve as the backbone for all of these prometastatic operations because their function as cell-cell and cell-matrix signal transducers are important for the heterogenous components of the microenvironment to communicate.

  1. Breast Cancer/Stromal Cells Coculture on Polyelectrolyte Films Emulates Tumor Stages and miRNA Profiles of Clinical Samples.

    Science.gov (United States)

    Daverey, Amita; Brown, Karleen M; Kidambi, Srivatsan

    2015-09-15

    In this study, we demonstrate a method for controlling breast cancer cells adhesion on polyelectrolyte multilayer (PEM) films without the aid of adhesive proteins/ligands to study the role of tumor and stromal cell interaction on cancer biology. Numerous studies have explored engineering coculture of tumor and stromal cells predominantly using transwell coculture of stromal cells cultured onto coverslips that were subsequently added to tumor cell cultures. However, these systems imposed an artificial boundary that precluded cell-cell interactions. To our knowledge, this is the first demonstration of patterned coculture of tumor cells and stromal cells that captures the temporal changes in the miRNA signature as the breast tumor develops through various stages. In our study we used synthetic polymers, namely poly(diallyldimethylammonium chloride) (PDAC) and sulfonated poly(styrene) (SPS), as the polycation and polyanion, respectively, to build PEMs. Breast cancer cells attached and spread preferentially on SPS surfaces while stromal cells attached to both SPS and PDAC surfaces. SPS patterns were formed on PEM surfaces, by either capillary force lithography (CFL) of SPS onto PDAC surfaces or vice versa, to obtain patterns of breast cancer cells and patterned cocultures of breast cancer and stromal cells. In this study, we utilized cancer cells derived from two different tumor stages and two different stromal cells to effectively model a heterogeneous tumor microenvironment and emulate various tumor stages. The coculture model mimics the proliferative index (Ki67 expression) and tumor aggressiveness (HER-2 expression) akin to those observed in clinical tumor samples. We also demonstrated that our patterned coculture model captures the temporal changes in the miRNA-21 and miRNA-34 signature as the breast tumor develops through various stages. The engineered coculture platform lays groundwork toward precision medicine wherein patient-derived tumor cells can be

  2. Laparoscopic local excision and rectoanal anastomosis for rectal gastrointestinal stromal tumor: modified laparoscopic intersphincteric resection technique.

    Science.gov (United States)

    Akiyoshi, Takashi; Ueno, Masashi; Fukunaga, Yosuke; Nagayama, Satoshi; Fujimoto, Yoshiya; Konishi, Tsuyoshi; Kuroyanagi, Hiroya

    2014-07-01

    Rectal GI stromal tumor is uncommon. Local excision with free resection margins provides adequate treatment, but extended surgery such as abdominoperineal resection has been frequently performed because of technical difficulties in the confined pelvic space. We aimed to report the technical details of a new method of local excision for rectal GI stromal tumor: the modified laparoscopic intersphincteric resection technique. This study was a retrospective analysis. This study was performed at a single institute. We included 3 patients with rectal GI stromal tumor who underwent this procedure following neoadjuvant imatinib therapy. Medial-to-lateral retroperitoneal dissection was begun near the sacral promontory, and rectal dissection while preserving autonomic nerves was performed down to the pelvic floor into the anal canal without dividing the inferior mesenteric artery. Dissection between the tumor and prostate was meticulously performed under laparoscopic magnified view. Next, circumferential connection between the laparoscopic and transanal dissections was performed through a transanal approach, and the rectum was extracted through the anus. Circular full-thickness local excision of the rectum and handsewn straight rectoanal anastomosis was performed. The safety and feasibility of this procedure were the primary outcomes measured by this study. The median operative time was 180 minutes, and the median estimated blood loss was 115 mL. There were no conversions or intraoperative complications, and there was 1 postoperative intestinal obstruction that recovered with conservative therapy. All patients had negative resection margins (R0), including 1 pathological complete response. The study was limited by the small number of patients. This modified laparoscopic intersphincteric resection technique is a novel and safe method for local excision of rectal GI stromal tumors located very close to the anus (see Video, Supplemental Digital Content 1, http

  3. Overexpression of matrix metalloproteinase-7 and -9 in NSCLC tumor and stromal cells: correlation with a favorable clinical outcome.

    Science.gov (United States)

    Stenvold, Helge; Donnem, Tom; Andersen, Sigve; Al-Saad, Samer; Al-Shibli, Khalid; Busund, Lill-Tove; Bremnes, Roy M

    2012-02-01

    Matrix metalloproteinases (MMPs) are considered important players in angiogenesis and cancer progression. Several drugs developed for targeting MMPs have until now been without clinical efficacy. As both malignant cells and cells of the surrounding stroma contribute to tumor growth, we have explored the impact of MMP-2, -7 and -9 expression in both the tumor and stromal compartment of non-small-cell lung cancers (NSCLC). From 335 unselected stage I to IIIA NSCLC carcinomas, duplicate tumor and tumor-associated stromal cores were collected in tissue microarrays (TMAs). Immunohistochemistry was used to detect the expression of MMP-2, -7 and -9 in tumor and stromal cells. In univariate analyses, high tumor cell MMP-7 expression (P=0.029) and high stromal MMP-9 expression (P=0.001) were positive prognostic factors. In the multivariate analysis, high tumor cell MMP-7 expression (HR 1.58, CI 1.08-2.32, P=0.020) and high stromal MMP-9 expression (HR 1.92, CI 1.25-2.96, P=0.003) were independent positive prognostic factors for disease-specific survival. High levels of MMP-7 in tumor cells and high levels of MMP-9 in tumor associated stroma were independent positive prognostic factors in NSCLC patients. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  4. Concurrent Male Gynecomastia and Testicular Hydrocele after Imatinib Mesylate Treatment of a Gastrointestinal Stromal Tumor

    OpenAIRE

    Kim, Hawk; Chang, Heung-Moon; Ryu, Min-Hee; Kim, Tae-Won; Sohn, Hee-Jung; Kim, So-Eun; Kang, Hye-Jin; Park, Sarah; Lee, Jung-Shin; Kang, Yoon-Koo

    2005-01-01

    We report a gastrointestinal stromal tumor (GIST) patient with male gynecomastia and testicular hydrocele after treatment with imatinib mesylate. A 42 yr-old male patient presented for management of hepatic masses. Two years earlier, he had undergone a small bowel resection to remove an intraabdominal mass later shown to be a GIST, followed by adjuvant radiation therapy. At presentation, CT scan revealed multiple hepatic masses, which were compatible with metastatic GIST, and he was prescribe...

  5. Gynecomastia during imatinib mesylate treatment for gastrointestinal stromal tumor: a rare adverse event

    OpenAIRE

    Liu, HeLi; Liao, GuoQing; Yan, ZhongShu

    2011-01-01

    Abstract Background Imatinib mesylate has been the standard therapeutic treatment for chronic myeloid leukemia, advanced and metastatic gastrointestinal stromal tumor (GIST). It is well tolerated with mild adverse effects. Gynecomastia development during the course of treatment has been rarely reported. Methods Ninety-eight patients with advanced or recurrent GIST were treated with imatinib mesylate. Among the fifty-seven male patients six developed gynecomastia during the treatment. The lesi...

  6. Gastrointestinal stromal tumor of large size, extragastrointestinal localization and different morphological features

    Directory of Open Access Journals (Sweden)

    Shpon’ka I.S.

    2015-09-01

    Full Text Available The problems of accurate verification of the gastro¬intestinal stromal tumor are relevant today for many reasons. Thus, the histological diagnosis is complicated by the morphological similarity of other gastrointestinal tract mesenchymal neoplasms and by histologicaly different zones within the same investigation. We present the situation with the above issues: the differential diagnosis includes an analysis of morphological criteria and received immunohisto-chemical reactions. Between immunophenotypes of histologicaly different zones principal difference is not revealed.

  7. Lactate is a mediator of metabolic cooperation between stromal carcinoma associated fibroblasts and glycolytic tumor cells in the tumor microenvironment

    International Nuclear Information System (INIS)

    Rattigan, Yanique I.; Patel, Brijesh B.; Ackerstaff, Ellen; Sukenick, George; Koutcher, Jason A.; Glod, John W.

    2012-01-01

    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 2 ) than under 20% O 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 13 C NMR spectroscopic measurements indicate that 13 C-lactate is converted to 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.

  8. Lactate is a mediator of metabolic cooperation between stromal carcinoma associated fibroblasts and glycolytic tumor cells in the tumor microenvironment

    Energy Technology Data Exchange (ETDEWEB)

    Rattigan, Yanique I.; Patel, Brijesh B. [Graduate School of Biomedical Sciences, The Cancer Institute of New Jersey, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08901 (United States); Department of Pharmacology, The Cancer Institute of New Jersey, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08901 (United States); Ackerstaff, Ellen [Department of Medical Physics, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065 (United States); Sukenick, George [Molecular Pharmacology and Chemistry Research Program, Sloan-Kettering Institute, 415 E 68th Street, New York, NY 10065 (United States); Koutcher, Jason A. [Department of Medical Physics, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065 (United States); Glod, John W. [Graduate School of Biomedical Sciences, The Cancer Institute of New Jersey, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08901 (United States); Department of Pharmacology, The Cancer Institute of New Jersey, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08901 (United States); Department of Pediatric Oncology, The Cancer Institute of New Jersey, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08901 (United States); 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.

  9. Stromal Cell-Derived Factor-1 Promotes Cell Migration, Tumor Growth of Colorectal Metastasis

    Directory of Open Access Journals (Sweden)

    Otto Kollmar

    2007-10-01

    Full Text Available In a mouse model of established extrahepatic colorectal metastasis, we analyzed whether stromal cellderived factor (SDF 1 stimulates tumor cell migration in vitro, angiogenesis, tumor growth in vivo. METHODS: Using chemotaxis chambers, CT26.WT colorectal tumor cell migration was studied under stimulation with different concentrations of SDF-1. To evaluate angiogenesis, tumor growth in vivo, green fluorescent protein-transfected CT26.WT cells were implanted in dorsal skinfold chambers of syngeneic BALB/c mice. After 5 days, tumors were locally exposed to SDF-1. Cell proliferation, tumor microvascularization, growth were studied during a further 9-day period using intravital fluorescence microscopy, histology, immunohistochemistry. Tumors exposed to PBS only served as controls. RESULTS:In vitro, > 30% of unstimulated CT26.WT cells showed expression of the SDF-1 receptor CXCR4. On chemotaxis assay, SDF-1 provoked a dose-dependent increase in cell migration. In vivo, SDF-1 accelerated neovascularization, induced a significant increase in tumor growth. Capillaries of SDF-1-treated tumors showed significant dilation. Of interest, SDF-1 treatment was associated with a significantly increased expression of proliferating cell nuclear antigen, a downregulation of cleaved caspase-3. CONCLUSION: Our study indicates that the CXC chemokine SDF-1 promotes tumor cell migration in vitro, tumor growth of established extrahepatic metastasis in vivo due to angiogenesis-dependent induction of tumor cell proliferation, inhibition of apoptotic cell death.

  10. Cystic changes in intraabdominal extrahepatic metastases from gastrointestinal stromal tumors treated with imatinib

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Hyo Cheol; Lee, Jeong Min; Choi, Seoung Hong; Han, Joon Koo; Choi, Byung Ihn [Seoul National University College of Medicine, Seoul (Korea, Republic of); Han, Heon; Kim, Sam Soo [Kangwon National University College of Medicine, Chuncheon (Korea, Republic of); Lee, Sang Hyun [National Cancer Center, Seoul (Korea, Republic of)

    2004-09-15

    This study was undertaken for the purpose of describing the CT features of intra-abdominal extra-hepatic metastases from gastrointestinal stromal tumors in patients who were treated with imatinib. Eleven patients with intra-abdominal extra-hepatic metastases from gastrointestinal stromal tumors, who were treated with imatinib between May 2001 and December 2003, were included in this study. The clinical findings and CT scans were retrospectively reviewed. The metastatic lesions were assessed according to the location, size (greatest diameter), attenuation, and the enhancing pattern before and after imatinib treatment. Prior to the treatment, the sizes and attenuation values of the metastatic lesions ranged from 5 to 20 cm and from 63 to 131 H, respectively. The metastatic lesions showed a heterogeneous enhancement pattern on the contrast-enhanced CT scans. After the treatment, the metastatic lesions became smaller in all 11 patients, and the corresponding attenuation value ranged from 15 to 51 H. The metastatic lesions became homogeneous and cystic in appearance on the follow-up CT scans, mimicking ascites. Intra-abdominal extra-hepatic metastases of patients with gastrointestinal stromal tumors treated with imatinib may appear as well-circumscribed cystic lesions on contrast-enhanced CT. These metastases are likely to become smaller and resemble ascites, but may persist indefinitely on the follow-up CT.

  11. Mesenchymal Stromal Cells Can Regulate the Immune Response in the Tumor Microenvironment

    Directory of Open Access Journals (Sweden)

    Alessandro Poggi

    2016-11-01

    Full Text Available The tumor microenvironment is a good target for therapy in solid tumors and hematological malignancies. Indeed, solid tumor cells’ growth and expansion can influence neighboring cells’ behavior, leading to a modulation of mesenchymal stromal cell (MSC activities and remodeling of extracellular matrix components. This leads to an altered microenvironment, where reparative mechanisms, in the presence of sub-acute inflammation, are not able to reconstitute healthy tissue. Carcinoma cells can undergo epithelial mesenchymal transition (EMT, a key step to generate metastasis; these mesenchymal-like cells display the functional behavior of MSC. Furthermore, MSC can support the survival and growth of leukemic cells within bone marrow participating in the leukemic cell niche. Notably, MSC can inhibit the anti-tumor immune response through either carcinoma-associated fibroblasts or bone marrow stromal cells. Experimental data have indicated their relevance in regulating cytolytic effector lymphocytes of the innate and adaptive arms of the immune system. Herein, we will discuss some of the evidence in hematological malignancies and solid tumors. In particular, we will focus our attention on the means by which it is conceivable to inhibit MSC-mediated immune suppression and trigger anti-tumor innate immunity.

  12. Gastrointestinal Stromal Cell Tumor (GIST) Presenting as an ...

    African Journals Online (AJOL)

    In second case an 53-year-old, postmenopausal, woman presented with abdominal fullness and constipation for the preceding 3-4 days. Physical examination and imaging studies revealed a huge pelvic mass, suggestive of a cystic degenerated myoma. An exploratory laparotomy revealed a large tumor originating from ...

  13. Obscure Gastrointestinal Bleeding Due to a Small Intestinal Gastrointestinal Stromal Tumor in a Young Adult

    Directory of Open Access Journals (Sweden)

    Mami Yamamoto

    2016-11-01

    Full Text Available The source of most cases of gastrointestinal bleeding is the upper gastrointestinal tract. Since bleeding from the small intestine is very rare and difficult to diagnose, time is required to identify the source. Among small intestine bleeds, vascular abnormalities account for 70–80%, followed by small intestine tumors that account for 5–10%. The reported peak age of the onset of small intestinal tumors is about 50 years. Furthermore, rare small bowel tumors account for only 1–2% of all gastrointestinal tumors. We describe a 29-year-old man who presented with obscure anemia due to gastrointestinal bleeding and underwent laparotomy. Surgical findings revealed a well-circumscribed lesion measuring 45 × 40 mm in the jejunum that initially appeared similar to diverticulosis with an abscess. However, the postoperative pathological diagnosis was a gastrointestinal stromal tumor with extramural growth.

  14. Gastrointestinal stromal tumor and leiomyoma of the ileum mimicking adnexal mass: a report of two cases.

    Science.gov (United States)

    Akman, Levent; Hurşitoğlu, Behiye Seda; Farajov, Rasim; Terek, Mustafa Coşan; Sezak, Murat; Şimşek, Deniz; Yılmaz, Hüseyin

    2015-01-01

    Adnexal masses are formations seen in women of all ages; they most often include cystic elements. Medical history, physical examination, different imaging methods, and tumor marker determinations must be used together for preoperative evaluation of an adnexal mass. Both benign and malignant tumors of the small intestine are more rarely encountered than malignant tumors of other gastrointestinal system components; although advanced imaging methods and other diagnostic techniques are used, they do not always allow these tumors to be differentiated from adnexal masses. We report here on two cases operated on with the preliminary diagnosis of an adnexal mass, in which the presence of a gastrointestinal stromal tumor and a leiomyoma of the ileum, respectively, was established.

  15. Small intestinal gastrointestinal stromal tumor in a young adult woman: a case report and review of the literature.

    Science.gov (United States)

    Manxhuka-Kerliu, Suzana; Sahatciu-Meka, Vjollca; Kerliu, Irma; Juniku-Shkololli, Argjira; Kerliu, Lloreta; Kastrati, Mevlyde; Kotorri, Vesa

    2014-09-28

    Gastrointestinal stromal tumor is the most common sarcoma of the gastrointestinal tract. We report a case of gastrointestinal stromal tumor in a small intestine, initially suspected for leiomyosarcoma given that gastrointestinal stromal tumors in young adult patients are limited due to their rarity. A 30-year-old Caucasian ethnic Albanian woman from Kosovo presented with abdominal pain, nausea and vomiting. Subsequently, the tumor was detected in her small intestine, as an infiltrating mass approximately 10 cm in diameter. The tumor was resected en bloc and duodenojejunal terminal-terminal anastomosis was performed. The tumor was a large, bulky, intramural mass, with fish-flesh to tan-brown appearance, as well as with foci of hemorrhage and necrosis. On histological examination the tumor showed transmural growth, deep infiltrative pattern and malignant feature, with mitotic count >5 per 50 high-power field, dense cellularity with plump spindle cells, and with eosinophilic cytoplasm within variably hyalinized and edematous stroma, skeinoid fibers (extracellular collagen globules) and foci of hemorrhage. In addition, the tumor was composed of areas with epithelioid morphology. The immunohistochemistry results showed high expression of proto-oncogene c-kit, CD117, CD34 and vimentin, whereas α-smooth muscle actin was focally positive. Desmin and S-100 protein were negative. Gastrointestinal stromal tumor should be included in the differential diagnoses of intestinal mesenchymal tumors presenting as a single mass in young female adults. Given that gastrointestinal stromal tumors in young adults represent a more heterogeneous group than gastrointestinal stromal tumor in pediatric cases, more effort should be made to investigate its pathogenesis and potentially more specific treatment.

  16. Hypertensive crisis during wide excision of gastrointestinal stromal cell tumor (GIST): Undiagnosed paraganglioma -A case report-.

    Science.gov (United States)

    Shinn, Helen Ki; Jung, Jong Kwon; Park, Jay Kim; Kim, Jong Hoon; Jung, In Young; Lee, Hong Sik

    2012-03-01

    Although paraganglioma (PGL), an extra-adrenal retroperitoneal pheochromocytoma (PHEO), is a rare catecholamine-secreting neuroendocrine tumor, it can cause severe hypertensive crisis during anesthesia or surgery if undiagnosed preoperatively. Extraluminal perigastric masses may be presumed to be gastrointestinal stromal tumors (GISTs) or soft tissue sarcomas even when histologic confirmation is not possible. Therefore, without a histologic diagnosis or symptoms of excessive catecholamine secretion, PGL may be mistaken for GIST. We report a case of preoperatively undiagnosed PGL which caused hypertensive crisis during anesthesia for retroperitoneal mass excision.

  17. Borderline gastric stromal tumor: diagnosis by ultrasound and computed tomography; Tumor estromal borderline del estomago diagnostico por imagen en ecografia y TC

    Energy Technology Data Exchange (ETDEWEB)

    Feijoo, R.; Rubio, P. J.; Lopez, J. I.; Borderias, A.; Placeres, A. [Hospita San Jorge. Huesca (Spain)

    2000-07-01

    Gastrointestinal stromal tumors (GIST) are a type of undifferentiated stromal tumor that is recently being diagnosed more frequently owing to the introduction of new immunohistochemical techniques. Their main feature, indispensable for the definitive diagnosis, is immunohistochemical evidence of the presence of CD34-positive cells. We present a case of GIST of borderline malignancy involving the outer wall of the stomach, describing the ultrasound and computed tomography images and their correlation with the pathological features. (Author) 8 refs.

  18. Synchronous Gastric Gastrointestinal Stromal Tumor and Colon Adenocarcinoma: A Case Report

    Directory of Open Access Journals (Sweden)

    Thivi Vasilakaki

    2014-01-01

    Full Text Available Gastrointestinal stromal tumors (GISTs represent the majority of primary mesenchymal tumors of the gastrointestinal tract. They are generally considered to be solitary tumors and therefore the synchronous occurrence with other primary malignancies of gastrointestinal track is considered a rare event. Here we present the case of a 75-year-old man admitted to our hospital with a 10-day history of gastrointestinal bleeding. Colonoscopy revealed an ulcerative mass of 4 cm in diameter in the ascending colon. Gastroscopy revealed a bulge in the gastric body measuring 1 cm in diameter with normal overlying mucosa. Surgical intervention was suggested and ileohemicolectomy with regional lymph node resection along with gastric wedge resection was performed. Pathologic examination of the ascending colon mass showed an invasive moderately differentiated adenocarcinoma stage III B (T3N1M0. Grossly resected wedge of stomach showed a well circumscribed intramural tumor which microscopically was consistent with essentially benign gastrointestinal stromal tumor (according to Miettinen criteria. The patient did not receive additional treatment. Two years later the patient showed no evidence of recurrence or metastasis.

  19. Drug repurposing identifies a synergistic combination therapy with imatinib mesylate for gastrointestinal stromal tumor.

    Science.gov (United States)

    Pessetto, Ziyan Y; Ma, Yan; Hirst, Jeff J; von Mehren, Margaret; Weir, Scott J; Godwin, Andrew K

    2014-10-01

    Gastrointestinal stromal tumor (GIST) is a rare and therefore often neglected disease. Introduction of the kinase inhibitor imatinib mesylate radically improved the clinical response of patients with GIST; however, its effects are often short-lived, with GISTs demonstrating a median time-to-progression of approximately two years. Although many investigational drugs, approved first for other cancers, have been subsequently evaluated for the management of GIST, few have greatly affected the overall survival of patients with advanced disease. We employed a novel, focused, drug-repurposing effort for GIST, including imatinib mesylate-resistant GIST, evaluating a large library of FDA-approved drugs regardless of current indication. As a result of the drug-repurposing screen, we identified eight FDA-approved drugs, including fludarabine phosphate (F-AMP), that showed synergy with and/or overcame resistance to imatinib mesylate. F-AMP induces DNA damage, Annexin V, and caspase-3/7 activities as the cytotoxic effects on GIST cells, including imatinib mesylate-resistant GIST cells. F-AMP and imatinib mesylate combination treatment showed greater inhibition of GIST cell proliferation when compared with imatinib mesylate and F-AMP alone. Successful in vivo experiments confirmed the combination of imatinib mesylate with F-AMP enhanced the antitumor effects compared with imatinib mesylate alone. Our results identified F-AMP as a promising, repurposed drug therapy for the treatment of GISTs, with potential to be administered in combination with imatinib mesylate or for treatment of imatinib mesylate-refractory tumors. ©2014 American Association for Cancer Research.

  20. Atypical presentation of myoepithelial hamartoma in the antrum of the stomach, mimicking a gastrointestinal stromal tumor: a case report

    Directory of Open Access Journals (Sweden)

    Nabi Junaid

    2012-11-01

    Full Text Available Abstract Introduction A myoepithelial hamartoma is a very uncommon submucosal tumor of the stomach. In an atypical presentation in our case, it mimicked the clinical presentation of a gastrointestinal stromal tumor. To the best of our knowledge, it is the first case of a hamartoma of the stomach reported from Bangladesh and one of few cases described in the literature. Case presentation We describe the case of a 35-year-old Bengali man with recurrent epigastric pain and occasional vomiting with radiographic findings of a gut mass. An upper gastrointestinal endoscopy revealed a healed duodenal ulcer, deformed ‘D’ bulb and a submucosal swelling in his antrum. Ultrasonography and a contrast-enhanced computed tomography scan confirmed the presence of a well-defined, oval gut mass in his upper abdomen, compressing his duodenum. The mass had a mixed density and was considered to probably be a gastrointestinal stromal tumor. Ultrasonography-guided fine needle aspiration cytology was inconclusive. After resection at laparotomy, a histopathological examination revealed a myoepithelial hamartoma. These tumors are characterized by hypertrophic smooth muscle bands surrounding varied epithelial elements, which may be arranged in diverse patterns such as simple glandular structure, Brunner’s gland, pancreatic ducts and sometimes pancreatic acini. This case report is complemented by a literature review relating to the atypical presentation. Conclusion Gut masses need to be investigated thoroughly and the possibility of rare tumors should not be excluded. Although the recommended treatment for such lesions is limited resection, radical procedures such as a pancreaticoduodenectomy are often performed when the lesion occurs in the periampullary area because of preoperative misdiagnosis as a carcinoma. Therefore, it is essential for clinicians to maintain current knowledge of the lesion to avoid inaccurate diagnosis and prevent unnecessary surgery.

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

    Directory of Open Access Journals (Sweden)

    Yoko Yamamoto

    2015-01-01

    Full Text Available 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.

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

    Science.gov (United States)

    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.

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

    Directory of Open Access Journals (Sweden)

    Sung Jin Oh

    2016-04-01

    Full Text Available 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.

  4. Spontaneous Rupture of Recurrent Gastrointestinal Stromal Tumor Associated with Neurofibromatosis Type 1

    Directory of Open Access Journals (Sweden)

    Shin-Mae Wang

    2005-11-01

    Full Text Available The incidence of gastrointestinal stromal tumor (GIST among neurofibromatosis type 1 (NF-1 patients is approximately 3.9–25%, and this relationship is generally considered to be non-coincidental. We report a patient with NF-1 who underwent laparotomy 3 times due to recurrent intra-abdominal tumor rupture with internal bleeding in the space of 13 years. The pathologic diagnoses were schwannoma, malignant peripheral nerve sheath tumor and GIST. Because of the similar histologic features of these tumors, we considered them to be of the same nature. Immunohistochemical staining can help in the differential diagnosis. We suggest that NF-1 patients with gastrointestinal symptoms receive further survey to rule out GISTs.

  5. Tomographic findings of gastric gastrointestinal stromal tumor: a 14-case study

    International Nuclear Information System (INIS)

    Pelandre, Gustavo Lemos; Djahjah, Maria Celia; Nobre, Luiz Felipe; Gasparetto, Emerson Leandro; Marchiori, Edson; Pereira, Bruno Vilhena; Valadao, Marcus; Linhares, Eduardo

    2008-01-01

    Objective: The purpose of this study was to describe the tomographic findings of gastric gastrointestinal stromal tumor. Materials and methods: Fourteen patients with histopathologically and immunohistochemically confirmed gastric gastrointestinal stromal tumors, who had already been submitted to computed tomography scans before the treatment, were evaluated in the period between January 1999 and December 2006. The following tomographic variables were analyzed: lesion topography, size/dimensions, homogeneity, contour, margins, morphology, pattern and intravenous contrast-enhancement intensity, growth pattern, invasion of adjacent organs, presence of ulceration, fistula, calcifications, mesenteric fat infiltration, lymphadenomegaly and presence of distant metastasis. Results: Tumors were found in the body (57.1%) or in the gastric fundus (42.9%), with sizes ranging between 6.0 cm and 23.0 cm (mean, 11.5 cm). Predominantly extra luminal growth was observed in 57.1% of cases and intra/extra luminal in 35.7%. Subtle contrast-enhancement was observed in 50%, moderate in 50%, and heterogeneous in 64.3% of cases. Additionally, central hypodensity was observed in 64.3%, invasion of adjacent organs in 42.9%, and hepatic metastasis in 7.2% of cases. Conclusion: In the present study, the majority of tumors were found in the gastric body, with an average size of 11.5 cm, presenting with central hypodensity, heterogeneous contrast-enhancement and predominantly extraluminal growth. (author)

  6. Extragastrointestinal stromal tumor presenting as a scrotal mass: an unusual case.

    Science.gov (United States)

    Kang, Seok-Ho; Kim, Myung-Joon; Park, Min-Gu; Park, Hong-Seok; Moon, Du-Geon; Sung, Deuk-Jae; Kim, Hyun-Chul; Chae, Yang-Seok; Cheon, Jun; Kim, Je-Jong

    2007-03-01

    We describe an unusual case of extragastrointestinal stromal tumor (EGIST) presenting as a scrotal mass. A 71-year-old man presented with a gradually enlarging scrotal mass with a 20-year duration. Physical examination revealed a huge (as large as volleyball), round, nontender mass occupying the whole scrotum, which was resected completely. Clinical and radiological findings did not comply with any other primary site disease. Under histological examination, the tumor showed a spindle cell pattern with low cellularity, absence of necrotic and mitotic features. immunohistochemical analysis revealed the tumor reactive for CD117 and CD34, while negative for smooth muscle actin, desmin and S-100 protein. To our knowledge, this is the first reported case of an EGIST involving the scrotum.

  7. Diagnostic criteria, specific mutations, and genetic predisposition in gastrointestinal stromal tumors

    Science.gov (United States)

    Bachet, Jean-Baptiste; Emile, Jean-François

    2010-01-01

    In 1998, gastrointestinal stromal tumor (GIST) emerged as a distinct oncogenetic entity and subsequently became a paradigm of targeted therapies in solid tumors. Diagnosis of GIST relies on both histology and immunohistochemistry. Ninety-five percent of GISTs express either KIT or DOG-1. Approximately 80%–90% of GISTs harbor gain-of-function mutations of either KIT or platelet-derived growth factor receptor alpha polypeptide (PDGFRA) receptor tyrosine kinase (RTK). More than 100 different mutations have been described, some of which are associated with specific clinical and/or histological characteristics. Detection of KIT or PDGFRA mutations is recommended in advanced GISTs because they are highly predictive of tumor response to RTK inhibitors, as well as in KIT-negative cases to confirm diagnosis. In most cases, GISTs are sporadic, but in rare cases, they are related with genetic predisposition, such as neurofibromatosis type 1, Carney triad, Carney–Stratakis syndrome, and inherited KIT or PDGFRA germline mutations. PMID:23776354

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

    Directory of Open Access Journals (Sweden)

    Papagiannopoulos K

    2008-05-01

    Full Text Available Abstract 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.

  9. Ileocolic intussusception secondary to gastrointestinal stromal tumor in a 61-year-old.

    Science.gov (United States)

    Gelabert, Christopher; Torradas, Jose; Nelson, Mathew

    2014-10-01

    Intussusception is a common emergency in patients age of 3 months to 5 years. In adults, the diagnosis is infrequent but must be considered in the clinical setting of abdominal pain and vomiting. We present a case of a 61-year-old woman presenting with epigastric abdominal pain and vomiting, diagnosed with intussusception secondary to gastrointestinal stromal tumor. Serial bedside ultrasound examinations uncovered the diagnosis of intussusception, confirmed by computed tomographic scan during a paroxysm of pain. Intussusception has a much higher predilection for neoplasms in adults, with a high morbidity and mortality, so early recognition is critical in improving patient outcomes.

  10. Circulating levels of cell adhesion molecule L1 as a prognostic marker in gastrointestinal stromal tumor patients

    Directory of Open Access Journals (Sweden)

    Schachner Melitta

    2011-05-01

    Full Text Available Abstract Background L1 cell adhesion molecule (CD171 is expressed in many malignant tumors and its expression correlates with unfavourable outcome. It thus represents a target for tumor diagnosis and therapy. An earlier study conducted by our group identified L1 expression levels in primary gastrointestinal stromal tumors (GIST as a prognostic marker. The aim of the current study was to compare L1 serum levels of GIST patients with those of healthy controls and to determine whether levels of soluble L1 in sera could serve as a prognostic marker. Methods Using a sensitive enzyme-linked immunosorbent assay (ELISA, soluble L1 was measured in sera of 93 GIST patients und 151 healthy controls. Soluble L1 levels were then correlated with clinicopathological data. Results Median levels of soluble L1 were significantly higher (p p Conclusion These results suggest that high soluble L1 levels predict poor prognosis and may thus be a promising tumor marker that can contribute to individualise therapy.

  11. Circulating levels of cell adhesion molecule L1 as a prognostic marker in gastrointestinal stromal tumor patients

    International Nuclear Information System (INIS)

    Zander, Hilke; Kaifi, Jussuf; Rawnaq, Tamina; Wedemeyer, Max von; Tachezy, Michael; Kunkel, Miriam; Wolters, Gerrit; Bockhorn, Maximilian; Schachner, Melitta; Izbicki, Jakob R

    2011-01-01

    L1 cell adhesion molecule (CD171) is expressed in many malignant tumors and its expression correlates with unfavourable outcome. It thus represents a target for tumor diagnosis and therapy. An earlier study conducted by our group identified L1 expression levels in primary gastrointestinal stromal tumors (GIST) as a prognostic marker. The aim of the current study was to compare L1 serum levels of GIST patients with those of healthy controls and to determine whether levels of soluble L1 in sera could serve as a prognostic marker. Using a sensitive enzyme-linked immunosorbent assay (ELISA), soluble L1 was measured in sera of 93 GIST patients und 151 healthy controls. Soluble L1 levels were then correlated with clinicopathological data. Median levels of soluble L1 were significantly higher (p < 0.001; Mann-Whitney U test) in sera of GIST patients compared to healthy individuals. Median soluble L1 levels were particularly elevated in patients with recurrence and relapse (p < 0.05; Mann Whitney U test). These results suggest that high soluble L1 levels predict poor prognosis and may thus be a promising tumor marker that can contribute to individualise therapy

  12. Outcome and Prognostic Factors in Endometrial Stromal Tumors: A Rare Cancer Network Study

    Energy Technology Data Exchange (ETDEWEB)

    Schick, Ulrike, E-mail: Ulrike.schick@icr.ac.uk [Department of Radiation Oncology, University Hospital, Geneva (Switzerland); Bolukbasi, Yasmin [Department of Radiation Oncology, Ege University Hospital, Izmir (Turkey); Thariat, Juliette [Department of Radiation Oncology, Antoine Lacassagne Center, Nice (France); Abdah-Bortnyak, Roxolyana; Kuten, Abraham [Department of Radiation Oncology, Rambam Medical Center, Haifa (Israel); Igdem, Sefik [Department of Radiation Oncology, Metropolitan Hospital, Istanbul (Turkey); Caglar, Hale [Department of Radiation Oncology, Marmara University Hospital, Istanbul (Turkey); Ozsaran, Zeynep [Department of Radiation Oncology, Ege University Hospital, Izmir (Turkey); Loessl, Kristina [Department of Radiation Oncology, University Hospital, Bern (Switzerland); Schleicher, Ursula [Department of Radiation Oncology, Dueren Hospital, Dueren (Germany); Zwahlen, Daniel [Department of Radiation Oncology, William Buckland Radiotherapy Centre, Melbourne (Australia); Villette, Sylviane [Department of Radiation Oncology, Rene Huguenin Center, Saint-Cloud (France); Vees, Hansjoerg [Department of Radiation Oncology, University Hospital, Geneva (Switzerland); Department of Radiation Oncology, Sion Hospital, Sion (Switzerland)

    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.

  13. Multiple malignant extragastrointestinal stromal tumors of the greater omentum and results of immunohistochemistry and mutation analysis: A case report

    OpenAIRE

    Kim, Jong-Han; Boo, Yoon-Jung; Jung, Cheol-Woong; Park, Sung-Soo; Kim, Seung-Joo; Mok, Young-Jae; Kim, Sang-Dae; Chae, Yang-Suk; Kim, Chong-Suk

    2007-01-01

    To report an extragastrointestinal stromal tumor (EGIST) that occurs outside the gastrointestinal tract and shows unique clinicopathologic and immunohistochemical features. In our case, we experienced multiple soft tissue tumors that originate primarily in the greater omentum, and in immunohistochemical analysis, the tumors showed features that correspond to malignant EGIST. Two large omental masses measured 15 cm x 10 cm and 5 cm × 4 cm sized and several small ovoid fragments were attached t...

  14. Gastrointestinal stromal tumor of the vermiform appendix mimicking Meckel's diverticulum: Case report with literature review.

    Science.gov (United States)

    Chun, Jae Min; Lim, Kyoung Hoon

    2016-01-01

    Gastrointestinal stromal tumors (GISTs) of the appendix are extremely rare. To date, only 15 cases have been reported in the English literature. Here, we present a new case of an appendiceal GIST with appendicitis. A 68-year-old man who complained of right lower abdominal tenderness underwent surgery for a cystic mass mimicking Meckel's diverticulum. Laparoscopy revealed a mass protruding from the proximal appendix with distal appendicitis. Complete resection with adequate margins was performed. Histology showed a spindle cell GIST without mitotic activity as well as a strong expression of CD117 and CD34. Primary appendiceal GIST occur at a very low rate and their symptoms are nonspecific. Accordingly, rare tumors of appendix including GISTs should be considered in the differential diagnosis of atypical symptoms or image findings. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

  15. ADAM12 produced by tumor cells rather than stromal cells accelerates breast tumor progression

    DEFF Research Database (Denmark)

    Frohlich, Camilla; Nehammer, Camilla; Albrechtsen, Reidar

    2011-01-01

    Expression of ADAM12 is low in most normal tissues, but is markedly increased in numerous human cancers, including breast carcinomas. We have previously shown that overexpression of ADAM12 accelerates tumor progression in a mouse model of breast cancer (PyMT). In the present study, we found...... that ADAM12 deficiency reduces breast tumor progression in the PyMT model. However, the catalytic activity of ADAM12 appears to be dispensable for its tumor-promoting effect. Interestingly, we demonstrate that ADAM12 endogenously expressed in tumor-associated stroma in the PyMT model does not influence...... tumor progression, but that ADAM12 expression by tumor cells is necessary for tumor progression in these mice. This finding is consistent with our observation that in human breast carcinoma ADAM12 is almost exclusively located in tumor cells and only rarely seen in the tumor-associated stroma. We...

  16. New developments in management of gastrointestinal stromal tumors: regorafenib, the new player in the team

    Directory of Open Access Journals (Sweden)

    Boichuk S

    2013-12-01

    Full Text Available Sergei Boichuk,1,2 Jessica L Rausch,1 Anette Duensing1,31Cancer Virology Program, University of Pittsburgh Cancer Institute, Hillman Cancer Center, Pittsburgh, PA, USA; 2Department of Pathology, Kazan State Medical University, Kazan, Russia; 3Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USAAbstract: Gastrointestinal stromal tumors (GISTs are the most common mesenchymal tumors of the gastrointestinal tract and the most frequent single type of sarcoma, at least in some geographical regions. They arise from the interstitial cells of Cajal (or a common progenitor cell. The vast majority of GISTs are characterized by oncogenically activating mutations in the KIT or platelet-derived growth factor receptor alpha (PDGFRA receptor tyrosine kinase genes. This molecular feature has been successfully exploited for therapeutic purposes, and as of a decade ago, GISTs have become the prototype of a solid tumor that can be targeted with small molecule kinase inhibitors. Imatinib mesylate (Gleevec®/Glivec® benefits more than 85% of patients with unresectable and/or metastatic GIST. Unfortunately, the majority of patients develop resistance to imatinib within the first 2 years of treatment and new therapeutic options are needed. Although the broad-range kinase inhibitor sunitinib malate (Sutent® has been the second-line therapy approved by the US Food and Drug Administration since 2006, it was not until recently (February 2013 that regorafenib (Stivarga® was approved as a third-line therapeutic agent for GIST. This review summarizes the development process of regorafenib for GIST and highlights its biochemical, pharmacologic, and clinical properties.Keywords: gastrointestinal stromal tumors, GIST, regorafenib

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

    Directory of Open Access Journals (Sweden)

    Jiang Z

    2016-06-01

    Full Text Available Zhiqiang Jiang, Jian Zhang, Zhi Li, Yingjun Liu, Daohai Wang, Guangsen Han Department of General Surgery, Affiliated Tumor Hospital, Zhengzhou University, Zhengzhou, People’s Republic of China Abstract: 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. Keywords: KIT, meta-analysis, prognosis, marker, therapy

  18. Tumores del estroma gastrointestinal: Estudio retrospectivo de 43 casos Gastrointestinal stromal tumors: a retrospective study of 43 cases

    Directory of Open Access Journals (Sweden)

    S. Alberto

    2008-11-01

    Full Text Available Introducción: los tumores del estroma gastrointestinal (GIST son poco frecuentes, con una incidencia de 10 a 20 casos por millón de habitantes y año. Aparecen en todo el tubo digestivo, mesenterio o epiplón adyacente; siendo más frecuentes en el estómago (60-70%; también pueden aparecer en el intestino delgado (20-25%, colon y recto (5% y esófago (Background: gastrointestinal stromal tumors (GISTs are rare (10 to 20/million. They exist in the whole digestive system and its surroundings, and are most common in the stomach (70%, followed by the small intestine (20-25%, colon and rectum (5%, and esophagus (< 5%. Their clinical presentation varies from small, incidentally found nodules to large and aggressive tumors. Nowadays GISTs are classified according to Fletcher's classification. Objective: to review the features of our GIST population. Methods: a retrospective study of GIST patients identified by immunohistochemical criteria, from 1997 to December 2007, and classified according to Fletcher's criteria. Results: 43 patients were included (24 men, 19 women with a mean age of 62.7 years. Gastric GISTs (20 cases, 46.5%, small intestine GISTs (18 cases, 41.9%; in 5 cases metastases of occult tumors were found. Eighteen cases had no symptoms. Tumors were classified according to Fletcher's criteria as high-risk (n = 19, intermediate-risk (n = 7, low-risk (n = 12, and indeterminate-risk (n = 5. Death occurred in 10 patients, and 13 patients had metastatic disease. Conclusions: our results are in accordance with the world literature, in which a majority of cases are men with gastric tumors. The 5-year survival rate was 42%. Fletcher's criteria were easily applicable criteria and could predict tumor behavior.

  19. Mutations in Exons 9 and 13 of KIT Gene Are Rare Events in Gastrointestinal Stromal Tumors

    Science.gov (United States)

    Lasota, Jerzy; Wozniak, Agnieszka; Sarlomo-Rikala, Maarit; Rys, Janusz; Kordek, Radzislaw; Nassar, Aziza; Sobin, Leslie H.; Miettinen, Markku

    2000-01-01

    Gastrointestinal stromal tumors (GISTs), the most common mesenchymal tumors of the gastrointestinal tract, typically express the KIT protein. Activating mutations in the juxtamembrane domain (exon 11) of the c-kit gene have been shown in a subset of GISTs. These mutations lead into ligand-independent activation of the tyrosine kinase of c-kit, and have a transforming effect in vitro. Several groups have studied the clinical implication of the c-kit mutation status of exon 11 in GISTs and a possible relationship between c-kit mutations and malignant behavior has been established. Recently, a 1530ins6 mutation in exon 9 and missense mutations, 1945A>G in exon 13 of the c-kit gene were reported. The frequency and clinical importance of these findings are unknown. In this study we evaluated 200 GISTs for the presence of mutations in exons 9 and 13 of c-kit. Six cases revealed 1530ins6 mutation in exon 9 and two cases 1945A>G mutation in exon 13. All tumors with mutations in exon 9 and 13 lacked mutations in exon 11 of c-kit. None of the analyzed tumors had more than one type of c-kit mutation. All but one of the eight tumors with mutations in exon 9 or 13 of the c-kit gene were histologically and clinically malignant. All four of six cases with exon 9 mutation of which location of primary tumor was known, were small intestinal, suggesting that this type of mutation could preferentially occur in small intestinal tumors. Exon 9 and 13 mutations seem to be rare, and they cover only a small portion (8%) of the balance of GISTs that do not have mutations in exon 11 of c-kit. This finding indicates that other genetic alterations may activate c-kit in GISTs, or that KIT is not activated by mutations in all cases. PMID:11021812

  20. Severe paraneoplastic hypoglycemia in a patient with a gastrointestinal stromal tumor with an exon 9 mutation: a case report

    International Nuclear Information System (INIS)

    Escobar, Guillermo A; Robinson, William A; Nydam, Trevor L; Heiple, Drew C; Weiss, Glen J; Buckley, Linda; Gonzalez, Rene; McCarter, Martin D

    2007-01-01

    Non-islet cell tumor induced hypoglycemia (NICTH) is a very rare phenomenon, but even more so in gastrointestinal stromal tumors. It tends to present in large or metastatic tumors, and can appear at any time in the progression of the disease. We present herein a case of NICTH in a GIST tumor and report an exon 9 mutation associated to it. A thirty nine year-old man with a recurrent, metastatic gastrointestinal stromal tumor presented to the hospital with nausea, dizziness, loss of consciousness, and profound hypoglycemia (20 mg/dL). There was no evidence of factitious hypoglycemia. He was stabilized with a continuous glucose infusion and following selective vascular embolization, the patient underwent debulking of a multicentric 40 cm × 25 cm × 10 cm gastrointestinal stromal tumor. After resection, the patient became euglycemic and returned to his normal activities. Tumor analysis confirmed excessive production of insulin-like growth factor II m-RNA and the precursor protein, 'big' insulin-like growth factor II. Mutational analysis also identified a rare, 6 bp tandem repeat insert (gcctat) at position 1530 in exon 9 of KIT. Optimal management of gastrointestinal stromal tumor-induced hypoglycemia requires a multidisciplinary approach, and surgical debulking is the treatment of choice to obtain immediate symptom relief. Imatinib or combinations of glucocorticoids and growth hormone are alternative palliative strategies for symptomatic hypoglycemia. In addition, mutations in exon 9 of the tyrosine kinase receptor KIT occur in 11–20% of GIST and are often associated with poor patient outcomes. The association of this KIT mutation with non-islet cell tumor induced hypoglycemia has yet to be established

  1. Personalized Medicine in Gastrointestinal Stromal Tumor (GIST: Clinical Implications of the Somatic and Germline DNA Analysis

    Directory of Open Access Journals (Sweden)

    Gloria Ravegnini

    2015-07-01

    Full Text Available Gastrointestinal stromal tumors (GIST are the most common mesenchymal tumors of the gastrointestinal tract. They are characterized by gain of function mutations in KIT or PDGFRA tyrosine kinase receptors, with their consequent constitutive activation. The gold standard therapy is imatinib that offers a good and stable response for approximately 18–36 months. However, resistance is very common and it is vital to identify new biomarkers. Up until now, there have been two main approaches with focus to characterize novel targets. On the one hand, the focus is on the tumor genome, as the final clinical outcome depends mainly from the cancer specific mutations/alterations patterns. However, the germline DNA is important as well, and it is inconceivable to think the patients response to the drug is not related to it. Therefore the aim of this review is to outline the state of the art of the personalized medicine in GIST taking into account both the tumor DNA (somatic and the patient DNA (germline.

  2. [Gastrointestinal stromal tumors: clinical and instrumental diagnosis. Analysis of a review of the literature].

    Science.gov (United States)

    D'Amato, A; Cristaldi, M; Pronio, A M; Montesani, C; Ribotta, G

    1999-01-01

    From a personal experience of 23 treated gastrointestinal stromal tumor (GISTs), this study analyzed both clinical and diagnostic problems of this quite new nosological category. A this literature review provides a rigid selection of papers (scientific basis, statistic inference, type/quality of the journal, etc.); only numerous series have been included (case reports were excluded) and only those published after 1990. Three-hundred-seventy-five cases have therefore been selected. Starting and late symptoms/signs and diagnostic tests employed were analyzed. Results show 1) a relevant GIST quantity (approx. 30%) is casually discovered, during operations carried out for other pathologies or diagnostic tests for other indications; 2) poor correlation between site of the tumor and clinical manifestations; 3) a positive correlation between tumor diameter and presence of symptoms/signs seems to exists. The accuracy of different diagnostic tests is reported. No specific symptoms/signs have been isolated; this kind of tumor is often accidentally found. An analysis of different diagnostic tests available today shows the very important role of endoscopic ultra-sound, together with CT and MRI.

  3. Response to imatinib rechallenge in a patient with a recurrent gastrointestinal stromal tumor after adjuvant therapy: a case report

    Directory of Open Access Journals (Sweden)

    Kang Yoon-Koo

    2011-10-01

    Full Text Available Abstract Introduction Adjuvant imatinib improves recurrence-free survival of patients following resection of primary KIT-positive gastrointestinal stromal tumors. However, it is unknown whether patients who previously received adjuvant imatinib therapy will respond to imatinib rechallenge as treatment for recurrent disease. Here we present the first report documenting the benefits of imatinib rechallenge in a patient previously exposed to imatinib during adjuvant treatment. Case presentation A 51-year-old Asian woman with a wedge-resected primary gastric gastrointestinal stromal tumor at high risk of relapse underwent two years of adjuvant treatment with imatinib. Only 10 months after the completion of adjuvant imatinib treatment, a computed tomography scan revealed gastrointestinal stromal tumor recurrence in this patient, with multiple peritoneal nodules in the upper abdomen being detected. Our patient was rechallenged with imatinib 400 mg/day and had a partial response after one month of treatment. Imatinib rechallenge was well tolerated by our patient; the only adverse events she experienced were grade 1 edema, anemia and fatigue. Our patient maintained a partial response two years and six months after the imatinib rechallenge. However, computed tomography scans three months later showed that our patient had disease progression. Conclusions This case report demonstrates that a patient with a gastrointestinal stromal tumor who had previously received adjuvant imatinib therapy responded to imatinib rechallenge as treatment for her recurrent disease. These results indicate that imatinib sensitivity can be maintained in a patient with previous exposure to adjuvant imatinib therapy.

  4. Soft tissue calcification secondary to imatinib mesylate in a patient with gastrointestinal stromal tumor.

    Science.gov (United States)

    Enck, Robert E; Abushahin, Fadi; Bossaer, John B

    2014-04-01

    Imatinib mesylate has been associated with the changes in bone turnover. We report a case of the development of tissue calcification in a patient on long-term therapy with this drug. A 48-year-old male patient with gastrointestinal stromal tumor and liver metastasis complained of abdominal pain. His treatment included hepatic artery chemoembolization and partial hepatectomy in addition to chronic imatinib mesylate for 4 years. On physical examination, he had a peritoneal mass just beneath the laparotomy incision scar that, after resection, was found to be dystrophic bone formation. Based on the previous studies suggesting bone changes due to chronic therapy with imatinib mesylate, we believe that the patient's new bone formation was causally related to the use of this drug. To our knowledge, there are no similar reported cases in the literature.

  5. Endoscopic ultrasonographic characteristics of gastric schwannoma distinguished from gastrointestinal stromal tumor.

    Science.gov (United States)

    Park, Hyung-Chul; Son, Dong-Jun; Oh, Hyung-Hoon; Oak, Chan-Young; Kim, Mi-Young; Chung, Cho-Yun; Myung, Dae-Seong; Kim, Jong-Sun; Cho, Sung-Bum; Lee, Wan-Sik; Joo, Young-Eun

    2015-01-01

    Gastric schwannoma (GS), a rare neurogenic mesenchymal tumor, is usually benign, slow-growing, and asymptomatic. However, GS is often misdiagnosed as gastrointestinal stromal tumors (GIST) on endoscopic and radiological examinations. The purpose of this study was to evaluate EUS characteristics of GS distinguished from GIST. A total of 119 gastric subepithelial lesions, including 31 GSs and 88 GISTs, who were histologically identified and underwent EUS, were enrolled in this study. We evaluated the EUS characteristics, including location, size, gross morphology, mucosal lesion, layer of origin, border, echogenic pattern, marginal halo, and presence of an internal echoic lesion by retrospective review of the medical records. GS patients comprised nine males and 22 females, indicating female predominance. In the gross morphology according to Yamada's classification, type I was predominant in GS and type III was predominant in GIST. In location, GSs were predominantly located in the gastric body and GISTs were predominantly located in the cardia or fundus. The frequency of 4th layer origin and isoechogenicity as compared to the echogenicity of proper muscle layer was significantly more common in GS than GIST. Although not statistically significant, marginal halo was more frequent in GS than GIST. The presence of an internal echoic lesion was significantly more common in GIST than GS. The EUS characteristics, including tumor location, gross morphology, layer of origin, echogenicity in comparison with the normal muscle layer, and presence of an internal echoic lesion may be useful in distinguishing between GS and GIST.

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

    Science.gov (United States)

    Muñoz, Mario; Ramirez, Pedro T; Echeverri, Carolina; Alvarez, Luis Guillermo; Palomino, Maria Alejandra; Pareja, Luis René

    2012-01-01

    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). 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. 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%. GISTs are uncommon; however, they should be considered in the differential diagnosis of patients presenting with an abdominal or pelvic mass.

  7. Development of nano radiopharmaceutical based on Bevacizumab labelled with Technetium-99m for early diagnosis of gastrointestinal stromal tumor

    International Nuclear Information System (INIS)

    Braga, Thais Ligiero

    2015-01-01

    The development of new radiopharmaceuticals is an essential activity to improve nuclear medicine, and essential for the early and effective diagnosis of oncological diseases. Among the various possibilities current research in the world, the radiopharmaceuticals to chemotherapeutic base may be the most effective in detecting tumors, particularly Gastrointestinal Stromal Tumor (GIST), the Metastatic Renal Cell Carcinoma and neuroendocrine pancreatic tumors. However, difficulties in directing, as well as adhesion of the radiopharmaceutical in the desired location, are currently the main problems in the early detection and treatment of some of these tumors. Advances in the field of nanotechnology, particularly in recent years, indicate significant contribution to overcoming these obstacles, particularly in the implementation of molecular barriers as well as the functionalization of the nanoparticles, thereby improving targeting by the use of surface nucleotides, and the increased adhesion, which facilitates the release of the drug and therefore increases the chances of early diagnosis and more effective treatment. This study aimed to the production, characterization and evaluation of cytotoxicity, as well as in vivo biodistribution test Bevacizumab nanoparticles labeled with Technetium-99m radionuclide for detection of type GIST tumors. Bevacizumab was encapsulated in the form of nanoparticles by the emulsification method using double poly-acetic acid and polyvinyl alcohol polymers (PLA / PVA) at a concentration of 2% of the monoclonal antibody. The characterization of the nanoparticles was performed by the technique of scanning electron microscopy (SEM). The cytotoxicity assessment was performed by XTT assay with various cell lines of solid tumor cells. The labeling with technetium-99m was done by the direct method, and its yield determined by paper chromatography using paper Whatmam 1 as the stationary phase and acetone as mobile phase. In the biodistribution study

  8. Brainstem tumors: Current management and future directions

    Directory of Open Access Journals (Sweden)

    Pablo F Recinos

    2012-01-01

    Full Text Available Tumors arising in the brainstem comprise 10-20% of all pediatric central nervous system (CNS tumors and account for a small percentage in adults. The prognosis for these tumors was considered uniformly poor prior to the era of modern neuroimaging and the location was fraught with disaster being considered a ′no man′s land′ for neurosurgeons. Following the introduction of advanced imaging modalities and neurophysiological monitoring, striking progress has occurred in the management of these lesions. Brainstem tumors are presently classified based on their anatomic location, focality, and histopathology. This article reviews the current classification of brainstem tumors, current management options, and future directions in the treatment for these rare tumors.

  9. A rare giant gastrointestinal stromal tumor of the stomach traversing the upper abdomen: a case report and literature review

    Directory of Open Access Journals (Sweden)

    Zhou Lei

    2012-04-01

    Full Text Available Abstract We present the case of a 66-year-old woman with a huge gastrointestinal stromal tumor of the stomach that traversed her upper abdomen. The predominant abdominal sign was a huge, palpable mass, but there were no other distinctive findings in her physical examination or her routine blood workup, including biochemical markers. It was difficult to judge the origin of the mass upon imaging. Furthermore, radiological findings revealed that the mass had a complex relationship with many major blood vessels. An exploratory laparotomy revealed a huge tumor protruding from the anterior wall of the stomach fundus, on the lesser curvature of the stomach, measuring approximately 21 × 34 × 11 cm in diameter and weighing 5.5 kg. A complete resection was performed and the tumor was characterized on immunohistochemistry as a gastrointestinal stromal tumor of the stomach. Preoperative diagnosis of gastrointestinal stromal tumors can be difficult, and we hope that the presentation of this rare case and literature review will benefit other diagnosing clinicians having similar problems.

  10. Meta-analysis of laparoscopic vs. open resection of gastric gastrointestinal stromal tumors.

    Directory of Open Access Journals (Sweden)

    Liangying Ye

    Full Text Available This meta-analysis compared laparoscopic surgery (LAP and open resection (OPEN for the treatment of gastric gastrointestinal stromal tumors (GISTs with regard to feasibility and safety.We searched PubMed, Embase, and Web of Science for studies published before March 2016 comparing the LAP and OPEN procedures for GISTs. RevMan 5.1 software was used for the meta-analysis.In total, 28 studies met the inclusion criteria for the meta-analysis. The mean tumor sizes in the OPEN and LAP groups were 4.54 and 5.67 cm. Compared with the OPEN patients, the LAP patients experienced shorter surgical times (P = 0.05, less blood loss (P5 cm, the present study did not report significant differences in operation time (P = 0.93, postoperative complications (P = 0.30, or recurrence rate (P = 0.61 between the two groups, though LAP was associated with favorable results regarding blood loss (P = 0.03 and hospital stay (P5 cm, no significant difference was detected between LAP and OPEN if patient selection and intraoperative decisions were carefully considered.

  11. Concurrent Male Gynecomastia and Testicular Hydrocele after Imatinib Mesylate Treatment of a Gastrointestinal Stromal Tumor

    Science.gov (United States)

    Kim, Hawk; Chang, Heung-Moon; Ryu, Min-Hee; Kim, Tae-Won; Sohn, Hee-Jung; Kim, So-Eun; Kang, Hye-Jin; Park, Sarah; Lee, Jung-Shin

    2005-01-01

    We report a gastrointestinal stromal tumor (GIST) patient with male gynecomastia and testicular hydrocele after treatment with imatinib mesylate. A 42 yr-old male patient presented for management of hepatic masses. Two years earlier, he had undergone a small bowel resection to remove an intraabdominal mass later shown to be a GIST, followed by adjuvant radiation therapy. At presentation, CT scan revealed multiple hepatic masses, which were compatible with metastatic GIST, and he was prescribed imatinib 400 mg/day. During treatment, he experienced painful enlargement of the left breast and scrotal swelling. Three months after cessation of imatinib treatment, the tumors recurred, and, upon recommencing imatinib, he experienced painful enlargement of the right breast and scrotal swelling. He was diagnosed with male gynecomastia caused by decreased testosterone and non-communicative testicular hydrocele. He was given androgen support and a hydrocelectomy, which improved his gynecomastia. The mechanism by which imatinib induces gynecomastia and hydrocele is thought to be associated with an inhibition of c-KIT and platelet-derive growth factor. This is the first report, to our knowledge, describing concurrent male gynecomastia and testicular hydrocele after imatinib treatment of a patient with GIST. PMID:15953881

  12. Endometrioid adenocarcinoma associated with endometrial stromal sarcoma: A rare, often unrecognized collision tumor

    Directory of Open Access Journals (Sweden)

    Grace Kim

    2015-08-01

    Full Text Available We are reporting 3 cases of the uterine corpus with collision of endometrioid adenocarcinoma (EAC with endometrial stromal sarcoma (ESS. The patients' ages ranged from 36 to 59 years old. The major clinical presentation was abnormal uterine bleeding. Microscopically, all 3 cases presented with 2 separate components, EAC Grade 1 and ESS (one low grade and two high grades. The EAC component ranged from 10% to 70%, and the ESS component ranged from 30% to 70% of total tumor volume. The EAC component was stage 1A in two cases and stage II in one case. The ESS component was stages IA, IIB, and IIIB. Adjuvant hormonal therapy was administrated to one patient while a second patient was treated with chemo/radiation therapy. Two patients were still alive with no evidence of disease at 4 years post-therapy. One patient was lost for follow-up. Collision tumor should be distinguished from carcinosarcoma due to its different treatment modality, outcome and, prognosis.

  13. Three cases of bone metastases in patients with gastrointestinal stromal tumors

    Directory of Open Access Journals (Sweden)

    Maurizio Zompatori

    2011-04-01

    Full Text Available Gastrointestinal stromal tumors (GISTs are rare, but represent the most common mesenchymal neoplasms of the gastrointestinal tract. Tumor resection is the treatment of choice for localized disease. Tyrosine kinase inhibitors (imatinib, sunitinib are the standard therapy for metastatic or unresectable GISTs. GISTs usually metastasize to the liver and peritoneum. Bone metastases are uncommon. We describe three cases of bone metastases in patients with advanced GISTs: two women (82 and 54 years of age, and one man (62 years of age. Bones metastases involved the spine, pelvis and ribs in one patient, multiple vertebral bodies and pelvis in one, and the spine and iliac wings in the third case. The lesions presented a lytic pattern in all cases. Two patients presented with multiple bone metastases at the time of initial diagnosis and one patient after seven years during the follow-up period. This report describes the diagnosis and treatment of the lesions and may help clinicians to manage bones metastases in GIST patients.

  14. Spectral Computed Tomography Imaging of Gastric Schwannoma and Gastric Stromal Tumor.

    Science.gov (United States)

    Liu, Jianli; Chai, Yanjun; Zhou, Junlin; Dong, Chi; Zhang, Wenjuan; Liu, Bin

    Gastric schwannomas (GSs) and gastrointestinal stromal tumors (GSTs) are grossly similar submucosal neoplasms with different prognoses. We explored the value of spectral computed tomography (CT) to distinguish between them. Patients diagnosed with GS or GST at Lanzhou University Second Hospital, China, between May 2013 and June 2015 were included retrospectively. The subjects underwent spectral CT examination before surgery and had histologically confirmed diagnosis of GS or GST. Twelve patients with GS (3 men; 9 women; mean [SD] age, 47.0 [11.5] years) and 20 with GST (7 men; 13 women; mean [SD] age, 54.7 [9.9]) showed significant differences in terms of arterial phase (AP) at 70 keV (P < 0.001), portal phase (PP) at 70 keV (P = 0.002), AP iodine concentration, PP iodine concentration, AP water concentration, AP slope of spectral curve, and PP slope of spectral curve (all P < 0.001). Spectral CT may be useful for noninvasive diagnosis of submucosal tumors.

  15. The Role of {sup 18}F-fluorodeoxyglucose Positron Emission Tomography in Gastrointestinal Stromal Tumors

    Energy Technology Data Exchange (ETDEWEB)

    Yoo, Ie Ryung [College of Medicine, The Catholic University of Korea, Seoul (Korea, Republic of)

    2008-12-15

    Gastrointestinal stromal tumors (GIST) are the most common mesenchymal neoplasm of the gastrointestinal tract, and can be distinguished from the smooth muscle or neural tumors in approximately 95% of patients by expression of the KIT receptor tyrosine kinase (CD117). GISTs are known to have high malignant potential and none can be labeled definitely as benign. However, GISTs are unresponsive to standard sarcoma chemotherapy, and only complete surgical resection provides chance for cure. Although the imaging modality of choice is enhanced CT scan in patients with GIST, FDG PET can reflect the malignant potential of GIST. Clinical management of patients with GISTs has dramatically changed with the introduction of novel therapeutics, such as imatinib mesylate (Glivec). This has created a need to re-evaluate the existing criteria used to assess treatment response. FDG PET as functional imaging modality proved to be significantly more accurate than CT alone when assessing GIST response to imatinib. And, FDG PET and PET/CT have been found to be highly sensitive in detecting early response, and to be useful in predicting long-term response to imatinib in patients with recurrent or metastatic GISTs.

  16. Concurrent male gynecomastia and testicular hydrocele after imatinib mesylate treatment of a gastrointestinal stromal tumor.

    Science.gov (United States)

    Kim, Hawk; Chang, Heung-Moon; Ryu, Min-Hee; Kim, Tae-Won; Sohn, Hee-Jung; Kim, So-Eun; Kang, Hye-Jin; Park, Sarah; Lee, Jung-Shin; Kang, Yoon-Koo

    2005-06-01

    We report a gastrointestinal stromal tumor (GIST) patient with male gynecomastia and testicular hydrocele after treatment with imatinib mesylate. A 42 yr-old male patient presented for management of hepatic masses. Two years earlier, he had undergone a small bowel resection to remove an intraabdominal mass later shown to be a GIST, followed by adjuvant radiation therapy. At presentation, CT scan revealed multiple hepatic masses, which were compatible with metastatic GIST, and he was prescribed imatinib 400 mg/day. During treatment, he experienced painful enlargement of the left breast and scrotal swelling. Three months after cessation of imatinib treatment, the tumors recurred, and, upon recommencing imatinib, he experienced painful enlargement of the right breast and scrotal swelling. He was diagnosed with male gynecomastia caused by decreased testosterone and noncommunicative testicular hydrocele. He was given androgen support and a hydrocelectomy, which improved his gynecomastia. The mechanism by which imatinib induces gynecomastia and hydrocele is thought to be associated with an inhibition of c-KIT and platelet-derive growth factor. This is the first report, to our knowledge, describing concurrent male gynecomastia and testicular hydrocele after imatinib treatment of a patient with GIST.

  17. Gastric stromal tumor presenting as a right upper quadrant abdominal mass. Importance of a correct radiological differential diagnosis

    International Nuclear Information System (INIS)

    Tudela, X.; Garcia-Vila, J. H.; Jornet, J.

    2001-01-01

    Stromal tumors of the gastrointestinal tract encompass a group of neoplasms representing 1% to 3% of all digestive system tumors. When located in the stomach, their tendency to exhibit and exophytic growth pattern makes it necessary to establish the differential diagnosis with respect to other gastric tumors (lymphoma, exophytic adenocarcinoma) and nongastrointestinal masses. We present a case that illustrated the difficulties associated with the imaging diagnosis of these lesions and the importance of modern radiological techniques (helical computed tomography and magnetic resonance) and the correct interpretation on the part of radiologists to orient pathologists and clinicians toward the diagnosis and proper treatment. (Author) 10 refs

  18. Tumor associated stromal cells play a critical role on the outcome of the oncolytic efficacy of conditionally replicative adenoviruses.

    Directory of Open Access Journals (Sweden)

    M Verónica Lopez

    Full Text Available The clinical efficacy of conditionally replicative oncolytic adenoviruses (CRAd is still limited by the inefficient infection of the tumor mass. Since tumor growth is essentially the result of a continuous cross-talk between malignant and tumor-associated stromal cells, targeting both cell compartments may profoundly influence viral efficacy. Therefore, we developed SPARC promoter-based CRAds since the SPARC gene is expressed both in malignant cells and in tumor-associated stromal cells. These CRAds, expressing or not the Herpes Simplex thymidine kinase gene (Ad-F512 and Ad(I-F512-TK, respectively exerted a lytic effect on a panel of human melanoma cells expressing SPARC; but they were completely attenuated in normal cells of different origins, including fresh melanocytes, regardless of whether cells expressed or not SPARC. Interestingly, both CRAds displayed cytotoxic activity on SPARC positive-transformed human microendothelial HMEC-1 cells and WI-38 fetal fibroblasts. Both CRAds were therapeutically effective on SPARC positive-human melanoma tumors growing in nude mice but exhibited restricted efficacy in the presence of co-administered HMEC-1 or WI-38 cells. Conversely, co-administration of HMEC-1 cells enhanced the oncolytic efficacy of Ad(I-F512-TK on SPARC-negative MIA PaCa-2 pancreatic cancer cells in vivo. Moreover, conditioned media produced by stromal cells pre-infected with the CRAds enhanced the in vitro viral oncolytic activity on pancreatic cancer cells, but not on melanoma cells. The whole data indicate that stromal cells might play an important role on the outcome of the oncolytic efficacy of conditionally replicative adenoviruses.

  19. Tumor del estroma gastrointestinal del intestino delgado Gastrointestinal stromal tumor of small intestine

    Directory of Open Access Journals (Sweden)

    Magaly Marión Luna Gozá

    2011-12-01

    Full Text Available Los tumores del estroma gastrointestinal fueron catalogados originalmente como otros tumores (leiomioma, leiomioblastoma o leiomiosarcoma, debido a su apariencia histológica similar; sin embargo, los avances en la biología molecular y la inmunohistoquímica, han permitido diferenciarlos de otras neoplasias digestivas, y definirlos como una entidad clínica e histopatológica propia. Se presenta un paciente, de sexo femenino, de la raza negra, de 79 años de edad, con dolor abdominal de 3 días de evolución, que se había iniciado en fosa ilíaca derecha y luego se mantuvo en bajo vientre, acompañado de vómitos, fatiga y decaimiento. Se decide intervenir quirúrgicamente y se lleva al salón de operaciones con el diagnóstico de una apendicitis aguda, del muñón, tipo oclusiva en el anciano, sin descartar una oclusión por bridas. Al realizar laparotomía se encuentra sangre libre en cavidad que no coagula, y se observó tumor hemorrágico, pediculado, muy móvil, hacia íleon terminal. Se realiza exéresis de este, se resecan aproximadamente 5 cm de intestino delgado y se realiza sutura termino-terminal posteriormente. Se realizó amplia toillette de la cavidad peritoneal y el cierre habitual, con evolución satisfactoria, y con alta a los 7 días. Se mantiene asintomática al año y medio de operada, y la biopsia arrojó tumor de intestino delgado, de bajo grado de malignidad, de 5 cm de diámetro.The tumors of the gastrointestinal stroma were originally classified as other type of tumors (leiomyoma, leiomyobastoma or leiomyosarcoma due to it similar histological appearance; however, the advances in the molecular biology and the immunohistochemistry have allowed its differentiation of other digestive neoplasms and to define them as an own clinical and histopathological entity. This is the case of a black female patient aged 79 presenting with abdominal pain during 3 days of evolution started in the right iliac fossa and then it remains in

  20. A Gastrointestinal Stromal Tumor of the Stomach Demonstrating a Stepwise Progression from Low- to High-Grade Malignancy

    Directory of Open Access Journals (Sweden)

    Takahiko Nakajima

    2012-01-01

    Full Text Available We report a case of a gastrointestinal stromal tumor (GIST of the stomach that demonstrated a stepwise progression from low- to high-grade malignancy. The patient had been followed for a small gastric submucosal tumor that had turned malignant after 8 years of indolence, manifested by tarry stools. The tumor was enucleated, and gastric GIST was diagnosed. The most significant histological finding was that the tumor comprised two clearly demarcated areas, one with less aggressive characteristics and the other with highly aggressive characteristics. The patient exhibited multiple liver metastases 24 months after surgery. Imatinib mesylate was not administered throughout the clinical course because it was not available for clinical use at that time. The patient followed an unfavorable clinical course and died of liver dysfunction 55 months after surgery. Autopsy was performed. By comparing the immunohistochemical profiles of primary and metastatic tumors, it was established that only the tumor cells with highly aggressive characteristics had metastasized.

  1. Survival of gastrointestinal stromal tumor patients in the imatinib era: life raft group observational registry

    Directory of Open Access Journals (Sweden)

    Call Jerry

    2012-03-01

    Full Text Available Abstract Background Gastrointestinal stromal tumors (GIST, one of the most common mesenchymal tumors of the gastrointestinal tract, prior to routine immunohistochemical staining and the introduction of tyrosine kinase inhibitors, were often mistaken for neoplasms of smooth muscle origin such as leiomyomas, leiomyosarcomas or leiomyoblastomas. Since the advent of imatinib, GIST has been further delineated into adult- (KIT or PDGFRα mutations and pediatric- (typified by wild-type GIST/succinate dehydrogenase deficiencies types. Using varying gender ratios at age of diagnosis we sought to elucidate prognostic factors for each sub-type and their impact on overall survival. Methods This is a long-term retrospective analysis of a large observational study of an international open cohort of patients from a GIST research and patient advocacy's lifetime registry. Demographic and disease-specific data were voluntarily supplied by its members from May 2000-October 2010; the primary outcome was overall survival. Associations between survival and prognostic factors were evaluated by univariate Cox proportional hazard analyses, with backward selection at P Results Inflections in gender ratios by age at diagnosis in years delineated two distinct groups: above and below age 35 at diagnosis. Closer analysis confirmed the above 35 age group as previously reported for adult-type GIST, typified by mixed primary tumor sites and gender, KIT or PDGFRα mutations, and shorter survival times. The pediatric group ( Conclusions Pediatric- and adult-type GIST have been previously characterized in clinical settings and these observations confirm significant prognostic factors for each from a diverse real-world cohort. Additionally, these findings suggest that extra diligence be taken with "young adults" (aged 18-35 at diagnosis as pediatric-type GIST may present well beyond adolescence, particularly as these distinct sub-types have different causes, and consequently

  2. p16 Expression Differentiates High-Risk Gastrointestinal Stromal Tumor and Predicts Poor Outcome

    Directory of Open Access Journals (Sweden)

    Michael Schmieder

    2008-10-01

    Full Text Available Gastrointestinal stromal tumors (GISTs are characterized by alterations in genes involved in cell cycle regulation. Although p16 (INK4A have been extensively investigated in GISTs, there are still discrepancies regarding its prognostic value. Therefore, we evaluated the clinical occurrence, diagnostic and prognostic value of p16 staining in GIST. One hundred one patients (54 women and 47 men with a mean age of 64.1 years (range, 17–94 years were surgically treated for a GIST within a 10-year period. Of these patients, 28 (28% were affected by metastases (mean follow-up, 4.5 years. In 36 patients (36%, GIST occurred coincidentally with other malignancies. Expression of c-kit was confirmed in 97 GIST patients (96%. In patients with high-risk GIST, the expression of p16 expression was highly predictive for poor prognosis, i.e., the development of recurrence or metastases (P = .006 and poor survival (P = .004. In addition, the expression of p16 was highly predictive for reduction of the survival in patients who were affected by metastases or recurrence (P = .041. The disease-specific and disease-free 1-, 3-, and 5-year survival rate was 96%, 90%, and 85% and 81%, 77%, and 72%, respectively. Primary tumor state, tumor size, and high-risk classification were confirmed as relevant predictors for unfavorable prognosis in GIST (P < .001. Our results indicate that in high-risk GIST and in patients with recurrence or metastases, the expression of p16 is highly predictive for poor outcome. Thus, in addition to high-risk classification, p16 expression might be an indicator for “very high risk GIST.”

  3. Perspectives on testicular sex cord-stromal tumors and those composed of both germ cells and sex cord-stromal derivatives with a comparison to corresponding ovarian neoplasms.

    Science.gov (United States)

    Roth, Lawrence M; Lyu, Bingjian; Cheng, Liang

    2017-07-01

    Sex cord-stromal tumors (SCSTs) are the second most frequent category of testicular neoplasms, accounting for approximately 2% to 5% of cases. Both genetic and epigenetic factors account for the differences in frequency and histologic composition between testicular and ovarian SCSTs. For example, large cell calcifying Sertoli cell tumor and intratubular large cell hyalinizing Sertoli cell neoplasia occur in the testis but have not been described in the ovary. In this article, we discuss recently described diagnostic entities as well as inconsistencies in nomenclature used in the recent World Health Organization classifications of SCSTs in the testis and ovary. We also thoroughly review the topic of neoplasms composed of both germ cells and sex cord derivatives with an emphasis on controversial aspects. These include "dissecting gonadoblastoma" and testicular mixed germ cell-sex cord stromal tumor (MGC-SCST). The former is a recently described variant of gonadoblastoma that sometimes is an immediate precursor of germinoma in the dysgenetic gonads of patients with a disorder of sex development. Although the relationship of dissecting gonadoblastoma to the previously described undifferentiated gonadal tissue is complex and not entirely resolved, we believe that it is preferable to continue to use the term undifferentiated gonadal tissue for those cases that are not neoplastic and are considered to be the precursor of classical gonadoblastoma. Although the existence of testicular MGC-SCST has been challenged, the most recent evidence supports its existence; however, testicular MGC-SCST differs significantly from ovarian examples due to both genetic and epigenetic factors. Copyright © 2017 Elsevier Inc. All rights reserved.

  4. Impact of Rechallenge with Imatinib in Patients with Advanced Gastrointestinal Stromal Tumor after Failure of Imatinib and Sunitinib

    OpenAIRE

    Sawaki, Akira; Kanda, Tatsuo; Komatsu, Yoshito; Nishida, Toshirou

    2014-01-01

    Purpose. This retrospective, nonrandomized study investigated the effect of imatinib rechallenge plus best supportive care (BSC) on overall survival after imatinib and sunitinib treatment for patients with locally advanced or metastatic gastrointestinal stromal tumor (GIST). Methods. Twenty-six patients who had previously been exposed to both imatinib and sunitinib were enrolled in this study. The treatment regimen was BSC with or without imatinib, based on the patient's choice after discussi...

  5. Current evidence of epidermal barrier dysfunction and thymic stromal lymphopoietin in the atopic march

    Directory of Open Access Journals (Sweden)

    Mei Li

    2014-09-01

    Full Text Available It has long been observed that the development of asthma, allergic rhinitis and food allergy are frequently preceded by atopic dermatitis, a phenomenon known as the “atopic march”. Clinical, genetic and experimental studies have supported the fact that atopic dermatitis could be the initial step of the atopic march, leading to the subsequent development of other atopic diseases. This brief review will focus on the current evidence showing that epidermal barrier dysfunction and the keratinocyte-derived cytokine thymic stromal lymphopoietin play critical roles in the onset of the atopic march.

  6. Canine and human gastrointestinal stromal tumors display similar mutations in c-KIT exon 11

    International Nuclear Information System (INIS)

    Gregory-Bryson, Emmalena; Bartlett, Elizabeth; Kiupel, Matti; Hayes, Schantel; Yuzbasiyan-Gurkan, Vilma

    2010-01-01

    Gastrointestinal stromal tumors (GISTs) are common mesenchymal neoplasms in the gastrointestinal tract of humans and dogs. Little is known about the pathogenesis of these tumors. This study evaluated the role of c-KIT in canine GISTs; specifically, we investigated activating mutations in exons 8, 9, 11, 13, and 17 of c-KIT and exons 12, 14, and 18 of platelet-derived growth factor receptor, alpha polypeptide (PDGFRA), all of which have been implicated in human GISTs. Seventeen canine GISTs all confirmed to be positive for KIT immunostaining were studied. Exons 8, 9, 11, 13 and 17 of c-KIT and exons 12, 14, and 18 of PDGFRA, were amplified from DNA isolated from formalin-fixed paraffin-embedded samples. Of these seventeen cases, six amplicons of exon 11 of c-KIT showed aberrant bands on gel electrophoresis. Sequencing of these amplicons revealed heterozygous in-frame deletions in six cases. The mutations include two different but overlapping six base pair deletions. Exons 8, 9, 13, and 17 of c-KIT and exons 12, 14, and 18 of PDGFRA had no abnormalities detected by electrophoresis and sequencing did not reveal any mutations, other than synonymous single nucleotide polymorphisms (SNPs) found in exon 11 of c-KIT and exons 12 and 14 of PDGFRA. The deletion mutations detected in canine GISTs are similar to those previously found in the juxtamembrane domain of c-KIT in canine cutaneous mast cell tumors in our laboratory as well as to those reported in human GISTs. Interestingly, none of the other c-KIT or PDGFRA exons showed any abnormalities in our cases. This finding underlines the critical importance of c-KIT in the pathophysiology of canine GISTs. The expression of KIT and the identification of these activating mutations in c-KIT implicate KIT in the pathogenesis of these tumors. Our results indicate that mutations in c-KIT may be of prognostic significance and that targeting KIT may be a rational approach to treatment of these malignant tumors. This study further

  7. Malignant gastrointestinal stromal tumor presenting with hemoperitoneum in puerperium: report of a case with review of the literature

    Directory of Open Access Journals (Sweden)

    Vasilakaki Thivi

    2010-11-01

    Full Text Available Abstract Background Gastrointestinal stromal tumors (GISTs are mesenchymal tumors that develop in the wall of the gastrointestinal tract and their diagnosis during pregnancy or puerperium is extremely rare. Case A 28-year old patient presented with acute abdomen due to hemoperitoneum from a large mass arising of the small intestine with distended vessels on its top and a ruptured superficial vessel bleeding into the peritoneal cavity. The patient was at the tenth postpartum day of her first pregnancy. The preoperative diagnosis was a possible ovarian or uterine mass. After an emergency exploratory laparotomy a segmental bowel resection was performed, removing the tumor with a part of 3-cm of the small intestine. Histology revealed GIST with maximum diameter of 13 cm and mitotic rates more than 5 mitoses per 50 high power fields with some atypical forms, indicating a high risk malignancy. Immunohistochemical staining of the tumor tissue demonstrated strongly positive reactivity to CD 117 (c-kit and CD34 in almost all the tumor cells. The patient was treated with oral imatinib mesylate (Gleevec 400 mg daily for one year. Three years after surgery, the patient was alive without evidence of metastases or local recurrence. Conclusion Considering that only few patients with gastrointestinal stromal tumors have been reported in the obstetrical and gynecological literature, the awareness of such an entity by the obstetricians-gynecologists is necessary in order to facilitate coordinated approach with the general surgeons and oncologists for the optimal care of the patients.

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

    Science.gov (United States)

    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.

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

    Directory of Open Access Journals (Sweden)

    Ryota Niikura

    2016-05-01

    Full Text Available 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.

  10. Early onset imatinib mesylate-induced hepatotoxicity in a patient with gastrointestinal stromal tumors.

    Science.gov (United States)

    Yachoui, Ralph

    2014-01-01

    Imatinib mesylate is used for the treatment of patients with Philadelphia chromosome-positive chronic myeloid leukemia and gastrointestinal stromal tumors (GISTs). It has been associated with severe hepatotoxicity, which may lead to liver failure and death. Few cases of imatinib mesylate-induced liver failure have been reported; most of them were observed in patients treated for chronic myeloid leukemia. To date, 2 cases were reported in patients treated for GISTs. Elevation of liver function tests is usually observed during the first 2-3 months after the initiation of therapy. We report a 46-year-old woman with advanced GISTs who developed hepatotoxicity 11 days after the initiation of imatinib therapy. Before therapy with imatinib, her liver function tests were normal. She had no known risk factors for viral or alcoholic liver disease. Imatinib was her only regular medication, and she had not used acetaminophen or over-the-counter medications. Her serologic studies for hepatitis were all negative. One week after imatinib discontinuation, liver function tests improved significantly. The present report confirms the possibility of early onset imatinib mesylate-induced liver failure in patients treated for GISTs. Surveillance of liver function tests should start early after the initiation of treatment and during all the duration of therapy.

  11. Precocious puberty secondary to a mixed germ cell-sex cord-stromal tumor associated with an ovarian yolk sac tumor: a case report

    Directory of Open Access Journals (Sweden)

    Metwalley Kotb

    2012-06-01

    Full Text Available Abstract Introduction Ovarian tumors are the least common cause of sexual precocity in girls. Mixed germ cell-sex cord-stromal tumors associated with a yolk sac tumor of the ovary are rare neoplasms, of which only a small number of well-documented cases have been described so far. Here, we report precocious puberty in a four-year-old Egyptian girl caused by a mixed germ cell-sex cord-stromal tumor associated with a yolk sac tumor of the ovary. Case presentation A four-year-old Egyptian girl was referred to our pediatric endocrinology unit for evaluation of bilateral breast budding, pubic hair and vaginal bleeding. On examination, we found that her breast enlargement and pubic hair were compatible with Tanner III. A thorough workup revealed a large mass in her right ovary. Magnetic resonance imaging ofher brain showed that her pituitary gland was normal. A hormonal assay revealed high levels of estradiol, 280 to 375pmol/L; progesterone, 5.3 nmol/L; testosterone 38.9 pg/mL; and androstenedione, 4.1 ng/mL. Her basal and stimulated levels of luteinizing hormone and follicle-stimulating hormone were low. Tumor markers levels were high, with a total inhibin of 1,069U/L and an alpha-fetoprotein of 987 μg/L. Her chromosomes were normal (46XX. Our patient underwent an explorative laparotomy and a solid tumor localized to her right ovary was identified. A right salpingo-oophorectomy was performed and the histopathological diagnosis was a mixed germ cell-sex cord-stromal tumorwith a yolk sac tumor of the ovary. Postoperatively, she was started on treatment with chemotherapy. Our patient is doing well without evidence of tumor recurrence or metastasis during eight months of postoperative follow-up. Conclusion Although a mixed germ cell-sex cord-stromal tumor associated with a yolk sac tumor of the ovary is a rare occurrence, it should be considered in the differential diagnosis for a prepubescent girl with an abdominal mass and precocious puberty.

  12. Gynecomastia during imatinib mesylate treatment for gastrointestinal stromal tumor: a rare adverse event

    Directory of Open Access Journals (Sweden)

    Yan ZhongShu

    2011-11-01

    Full Text Available Abstract Background Imatinib mesylate has been the standard therapeutic treatment for chronic myeloid leukemia, advanced and metastatic gastrointestinal stromal tumor (GIST. It is well tolerated with mild adverse effects. Gynecomastia development during the course of treatment has been rarely reported. Methods Ninety-eight patients with advanced or recurrent GIST were treated with imatinib mesylate. Among the fifty-seven male patients six developed gynecomastia during the treatment. The lesions were confirmed by sonography. Sex hormone levels were determined in six patients with and without the presence of gynecomastia respectively. The patients with gynecomatia were treated with tamoxifene and the sex hormones were assayed before and after tamoxifene treatment. Results In patients with gynecomastia the lump underneath the bilateral nipples was 2.5 to 5 centimeters in diameter. Their serum free testosterone levels ranged between 356.61 and 574.60 ng/dl with a mean ± SD of 408.64 ± 82.06 ng/dl (95% CI 343.03~474.25 ng/dl, which is within the normal range. The level of serum estradiol was 42.89 ± 16.54 pg/ml (95% CI 29.66~56.12 pg/ml. Three patients had higher levels (43.79~71.21 pg/ml and the others' were within normal range of 27.00~34.91 pg/ml. Six patients without the development of gynecomastia had normal free testosterone. One patient died because of large tumor burden. The sex hormones had no significant changes before and after tamoxifene treatment.(P > 0.05 Conclusions Testosterone levels were not decreased in the six GIST patients with gynecomastia. Three patients had increased serum estradiol level which suggests that imbalance of sex hormones may be the cause of gynecomastia during treatment with imatinib mesylate.

  13. [Clinical experience of imatinib mesylate for metastatic or recurrent gastrointestinal stromal tumor].

    Science.gov (United States)

    Toyokawa, Takahiro; Yamashita, Yoshito; Yamamoto, Atsushi; Shimizu, Sadatoshi; Inoue, Tohru; Kanazawa, Akisige; Tsukamoto, Tadashi; Ikehara, Teruyuki; Nishiguchi, Yukio

    2014-01-01

    We examined the clinical results of 15 patients treated with imatinib mesylate for metastatic or recurrent gastrointestinal stromal tumors(GIST)at the Osaka City General Hospital. Treatment with imatinib was initiated at 400 mg daily; however, in case of severe adverse events, the dose was gradually reduced to 300 mg or 200 mg to reach a tolerable dose so that administration could be continued for as long as possible. Assessments were performed according to the Response Evaluation Criteria in Solid Tumors(RECIST)and Choi criteria. According to the assessment by the RECIST criteria, clinical response(CR)was observed in 1 patient; partial response(PR), in 5 patients; stable disease(SD), in 6 patients; and progressive disease(PD), in 3 patients; the response rate was 40%. However, as per the Choi criteria, CR was observed in 1 patient; PR, in 11 patients; SD, in 1 patient; and PD, in 2 patients; the response rate was 80%. The median period of progression-free survival was 2,031 days and the 5-year survival rate was 80.0%. Grade 3 or higher adverse reactions observed included leukopenia(1 case), neutropenia( 2 cases), and anemia(1 case). In 6 patients(40%), the dose of imatinib was reduced to 300 mg or less; however, no significant difference in progression-free survival was observed between the 200/300mg group and 400/800mg group. Choi criteria are useful in assessing the response of advanced GIST to imatinib mesylate, and reducing the dose of imatinib mesylate to 200/300mg daily might be sufficient for treating patients who experience severe adverse reactions.

  14. Efficacy and Economic Value of Adjuvant Imatinib for Gastrointestinal Stromal Tumors

    Science.gov (United States)

    Gronchi, Alessandro

    2013-01-01

    Objective. This article presents the clinical effectiveness and cost-effectiveness of the use of adjuvant imatinib mesylate for treating patients with localized primary gastrointestinal stromal tumors (GISTs) and discusses the impact of prolonged treatment with adjuvant imatinib on health care costs. Methods. A systematic review of the medical literature was conducted to explore recently reported clinical trials demonstrating the clinical benefit of adjuvant imatinib in GISTs, along with analyses discussing the economic impact of adjuvant imatinib. Results. Two phase III trials have demonstrated a significant clinical benefit of adjuvant imatinib treatment in GIST patients at risk of recurrence after tumor resection. Guidelines now suggest adjuvant treatment for at least 3 years in patients at high risk of recurrence. Despite this clinical effectiveness, prolonged use of adjuvant imatinib can lead to an increase in the risk for adverse events and to increased costs for both patients and health care systems. However, the increased cost is partially offset by cost reductions associated with delayed or avoided GIST recurrences. Three years of adjuvant treatment in high-risk patients was concluded to be cost-effective. Therefore, the careful selection of patients who are most likely to benefit from treatment can lead to improved clinical outcomes and significant cost savings. Conclusion. Although introducing adjuvant imatinib has an economic impact on health plans, this effect seems to be limited. Several analyses have demonstrated that adjuvant imatinib is more cost-effective for treating localized primary GISTs than surgery alone. In addition, 3 years of adjuvant imatinib is more cost-effective than 1 year of adjuvant therapy. PMID:23709752

  15. The role of p53 protein and MMP-2 tumor/stromal cells expression on progressive growth of ovarian neoplasms.

    Science.gov (United States)

    Grelewski, Piotr Grzegorz; Bar, Julia Krystyna

    2013-08-01

    The aim of our study was to evaluate p53 gene/protein status and MMP-2 expression in respect to ovarian tumors progress to define the role of these markers in the metastasis of ovarian carcinomas. MMP-2 and p53 alterations were evaluated on 80 malignant, 30 benign ovarian tumors, and 62 metastatic lesions by using HRM method for mutations in p53 gene and by using RT-PCR for mRNA MMP-2 level. Our data indicate that parallel expression of MMP-2 epithelial/stromal cells and p53 may enhance cells invasion and metastasis in ovarian carcinoma.

  16. Survival of gastrointestinal stromal tumor patients in the imatinib era: life raft group observational registry

    International Nuclear Information System (INIS)

    Call, Jerry; Walentas, Christopher D; Eickhoff, Jens C; Scherzer, Norman

    2012-01-01

    Gastrointestinal stromal tumors (GIST), one of the most common mesenchymal tumors of the gastrointestinal tract, prior to routine immunohistochemical staining and the introduction of tyrosine kinase inhibitors, were often mistaken for neoplasms of smooth muscle origin such as leiomyomas, leiomyosarcomas or leiomyoblastomas. Since the advent of imatinib, GIST has been further delineated into adult- (KIT or PDGFRα mutations) and pediatric- (typified by wild-type GIST/succinate dehydrogenase deficiencies) types. Using varying gender ratios at age of diagnosis we sought to elucidate prognostic factors for each sub-type and their impact on overall survival. This is a long-term retrospective analysis of a large observational study of an international open cohort of patients from a GIST research and patient advocacy's lifetime registry. Demographic and disease-specific data were voluntarily supplied by its members from May 2000-October 2010; the primary outcome was overall survival. Associations between survival and prognostic factors were evaluated by univariate Cox proportional hazard analyses, with backward selection at P < 0.05 used to identify independent factors. Inflections in gender ratios by age at diagnosis in years delineated two distinct groups: above and below age 35 at diagnosis. Closer analysis confirmed the above 35 age group as previously reported for adult-type GIST, typified by mixed primary tumor sites and gender, KIT or PDGFRα mutations, and shorter survival times. The pediatric group (< age 18 at diagnosis) was also as previously reported with predominantly stomach tumors, females, wild-type GIST or SDH mutations, and extended survival. 'Young adults' however formed a third group aged 18-35 at diagnosis, and were a clear mix of these two previously reported distinct sub-types. Pediatric- and adult-type GIST have been previously characterized in clinical settings and these observations confirm significant prognostic factors for each

  17. Distinct Patterns of Stromal and Tumor Expression of ROR1 and ROR2 in Histological Subtypes of Epithelial Ovarian Cancer

    Directory of Open Access Journals (Sweden)

    C.E. Henry

    2017-06-01

    Full Text Available OBJECTIVE: The ROR1 and ROR2 receptor tyrosine kinases have both been implicated in ovarian cancer progression and have been shown to drive migration and invasion. There is an increasing importance of the role of stroma in ovarian cancer metastasis; however, neither ROR1 nor ROR2 expression in tumor or stromal cells has been analyzed in the same clinical cohort. AIM: To determine ROR1 and ROR2 expression in ovarian cancer and surrounding microenvironment and examine associations with clinicopathological characteristics. METHODS: Immunohistochemistry for ROR1 and ROR2 was used to assess receptor expression in a cohort of epithelial ovarian cancer patients (n = 178. Results were analyzed in relation to clinical and histopathological characteristics and survival. Matched patient sample case studies of normal, primary, and metastatic lesions were used to examine ROR expression in relation to ovarian cancer progression. RESULTS: ROR1 and ROR2 are abnormally expressed in malignant ovarian epithelium and stroma. Higher ROR2 tumor expression was found in early-stage, low-grade endometrioid carcinomas. ROR2 stromal expression was highest in the serous subtype. In matched patient case studies, metastatic samples had higher expression of ROR2 in the stroma, and a recurrent sample had the highest expression of ROR2 in both tumor and stroma. CONCLUSION: ROR1 and ROR2 are expressed in tumor-associated stroma in all histological subtypes of ovarian cancer and hold potential as therapeutic targets which may disrupt tumor and stroma interactions.

  18. The inside mystery of jejunal gastrointestinal stromal tumor: a rare case report and review of the literature.

    Science.gov (United States)

    Dhull, A K; Kaushal, V; Dhankhar, R; Atri, R; Singh, H; Marwah, N

    2011-01-01

    Gastrointestinal stromal tumors (GISTs) are malignant and rare form of soft tissue sarcoma of the digestive tract. The incidence of gastrointestinal stromal tumors is very low Kramer et al. 2005 Jejunal GISTs are extremely rare. Here we present a rare case of jejunal GIST with unusually large size at presentation. The patient presented with severe abdomen pain, exophytic growth, and dimorphic anemia. Surgical resection of the tumor was carried out, and operative findings revealed a 15 × 10 cm growth, arising from serosal surface of jejunum, at the antimesenteric surface. Diagnosis in this case was made by subjecting the resected specimen to immunohistochemical analysis. In view of large size of the resected tumor, and high-risk histopathological features, imatinib mesylate 400 mg once daily was given as adjuvant chemotherapy. Patient is asymptomatic without any evidence of tumor recurrence after six months of postoperative followup. Imatinib as such is recommended in metastatic, residual or recurrent cases of GISTs or which are surgically not removable; however, recent recommendations suggests the use of imatinib mesylate after radical surgery in high-risk cases, because it has shown a significant decrease in the recurrence rate, and the Food and Drug Administration (FDA) has also approved the use of imatinib as adjuvant therapy after complete resection of localized, primary GIST.

  19. The Inside Mystery of Jejunal Gastrointestinal Stromal Tumor: A Rare Case Report and Review of the Literature

    Directory of Open Access Journals (Sweden)

    A. K. Dhull

    2011-01-01

    Full Text Available Gastrointestinal stromal tumors (GISTs are malignant and rare form of soft tissue sarcoma of the digestive tract. The incidence of gastrointestinal stromal tumors is very low Kramer et al. 2005 Jejunal GISTs are extremely rare. Here we present a rare case of jejunal GIST with unusually large size at presentation. The patient presented with severe abdomen pain, exophytic growth, and dimorphic anemia. Surgical resection of the tumor was carried out, and operative findings revealed a 15 × 10 cm growth, arising from serosal surface of jejunum, at the antimesenteric surface. Diagnosis in this case was made by subjecting the resected specimen to immunohistochemical analysis. In view of large size of the resected tumor, and high-risk histopathological features, imatinib mesylate 400 mg once daily was given as adjuvant chemotherapy. Patient is asymptomatic without any evidence of tumor recurrence after six months of postoperative followup. Imatinib as such is recommended in metastatic, residual or recurrent cases of GISTs or which are surgically not removable; however, recent recommendations suggests the use of imatinib mesylate after radical surgery in high-risk cases, because it has shown a significant decrease in the recurrence rate, and the Food and Drug Administration (FDA has also approved the use of imatinib as adjuvant therapy after complete resection of localized, primary GIST.

  20. Functional role of the Ca2+-activated Cl− channel DOG1/TMEM16A in gastrointestinal stromal tumor cells

    International Nuclear Information System (INIS)

    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

    2014-01-01

    DOG1, a Ca 2+ -activated Cl − 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 − 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 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

  1. The application of CO2-sensitive AIEgen in studying the synergistic effect of stromal cells and tumor cells in a heterocellular system.

    Science.gov (United States)

    Chen, Didi; Wang, Huan; Liu, Pai; Song, Linlin; Shi, Jianbing; Tong, Bin; Dong, Yuping

    2018-02-25

    Reciprocal signaling between stromal and tumor cells was believed to contribute to tumor cell proliferation and apoptosis in heterocellular systems. Herein we used the CO 2 -sensitive AIEgen as bioprobe to study the synergistic effect of stromal cells and tumor cells in a heterocellular system. The experimental results demonstrated that metabolic rates of living tumor cells in the co-culture system were still faster than that of stromal cell through the detection of CO 2 generation rate in living cell. All rates were, however, slower than that in homocellular system. It indicated that tumor cells would induce neighboring stromal cells to establish a common protection mechanism against foreign material invasion, which enhanced the cell activity and drug resistance. In addition, tumor cells in solid carcinoma exhibited delayed growth but less apoptosis in co-culture systems. Taken these results together, a bidirectional signaling pathway theory was proposed between tumor and stromal cells in co-culture system and could play a different and important role in anticancer drug molecules designs. Copyright © 2017 Elsevier B.V. All rights reserved.

  2. Ki67 and p53 in gastrointestinal stromal tumors - GIST Ki67 and p53 em tumores estromais gastrointestinais - GIST

    Directory of Open Access Journals (Sweden)

    Lúcio Roberto de Oliveira das Neves

    2009-06-01

    Full Text Available CONTEXT: Gastrointestinal stromal tumor (GIST is the most common mesenchymal tumor. Cellular proliferation and apoptosis is gaining importance for predicting prognosis in several cancers. OBJECTIVE: To investigate the Ki67 and p53 immunostaining in GISTs. METHODS: Specimens from 40 patients with GIST were assessed for immunohistochemical expression of Ki67 and p53. The tumors were divided according the risk of recurrence in two groups: I with high or intermediate risk and; II with low or very low risk. RESULTS: Among the 40 patients, 21 were men, the mean age was 56 years, 16 occurred in the small intestine and 13 in the stomach, 5 in the retroperitonium, 4 in the colon or rectum and 2 in the mesenterium. Thirty two tumors were from group I and 8 from group II. Half of the patients developed recurrence, being 90% of the group I (P = 0.114. The tumor Ki67 labelling index ranged from 0.02 to 0.35 (mean level 0.12. This index was marginally higher in the group I patients with recurrence (P = 0.09 compared to the patients of the same group without recurrence. p53 staining was expressed in 65% of the GISTs. A higher frequency of p53 and Ki67 had been found in the group I tumors when compared to the other group (P = 0.022; OR = 8.00 - IC 95%: 1.32-48.65. CONCLUSION: The most common site was the small intestine and 80% had a malignant potential justifying the high recurrence observed. No significant correlation was found between p53 and overall outcome of the patients. In group I patients, the evaluation Ki67LI may be a marker of prognosis. The positivity of both markers is higher among the patients with worst prognosis than in the others.CONTEXTO: Os tumores estromais gastrointestinais (GIST são os tumores mesenquimais mais frequentes. A proliferação intestinal e a apoptose são cada vez mais importantes na avaliação do prognóstico de diversos cânceres. OBJETIVO: Avaliar a imunoexpressão de Ki67 e p53 em GIST. MÉTODOS: Foram estudados a

  3. SSAT State-of-the-Art Conference: Current Surgical Management of Gastric Tumors.

    Science.gov (United States)

    Norton, Jeffrey A; Kim, Teresa; Kim, Joseph; McCarter, Martin D; Kelly, Kaitlyn J; Wong, Joyce; Sicklick, Jason K

    2018-01-01

    The current era of gastric surgery is marked by low morbidity and mortality rates, innovative strategies to approach resections with a minimally invasive fashion or hyperthermic intraperitoneal chemotherapy (HIPEC), as well as improved understanding of the biology of sporadic and hereditary stromal, neuroendocrine, and epithelial malignancies. In 2017, the Society for Surgery of the Alimentary Tract convened a State-of-the-Art Conference on Current Surgical Management of Gastric Tumors with both international experts and emerging leaders in the field of gastric surgery. Martin D. McCarter, MD of the University of Colorado discussed the current management of gastric gastrointestinal stromal tumors (GIST). Kaitlyn J. Kelly, MD of the University of California, San Diego discussed the management of gastric carcinoid tumors. Jeffrey A. Norton of Stanford University discussed recent advances in the management of gastric adenocarcinoma including a focus on hereditary diffuse gastric cancer (HDGC). Joseph Kim, MD of Stony Brook University discussed a systematic approach to minimally invasive gastrectomy for cancer. Joyce Wong, MD of Pennsylvania State University discussed the role for cytoreductive surgery (CRS) and HIPEC for gastric adenocarcinoma. This review provides gastrointestinal surgeons with a concise update on the current surgical management of gastric tumors.

  4. MixHMM: inferring copy number variation and allelic imbalance using SNP arrays and tumor samples mixed with stromal cells.

    Science.gov (United States)

    Liu, Zongzhi; Li, Ao; Schulz, Vincent; Chen, Min; Tuck, David

    2010-06-01

    Genotyping platforms such as single nucleotide polymorphism (SNP) arrays are powerful tools to study genomic aberrations in cancer samples. Allele specific information from SNP arrays provides valuable information for interpreting copy number variation (CNV) and allelic imbalance including loss-of-heterozygosity (LOH) beyond that obtained from the total DNA signal available from array comparative genomic hybridization (aCGH) platforms. Several algorithms based on hidden Markov models (HMMs) have been designed to detect copy number changes and copy-neutral LOH making use of the allele information on SNP arrays. However heterogeneity in clinical samples, due to stromal contamination and somatic alterations, complicates analysis and interpretation of these data. We have developed MixHMM, a novel hidden Markov model using hidden states based on chromosomal structural aberrations. MixHMM allows CNV detection for copy numbers up to 7 and allows more complete and accurate description of other forms of allelic imbalance, such as increased copy number LOH or imbalanced amplifications. MixHMM also incorporates a novel sample mixing model that allows detection of tumor CNV events in heterogeneous tumor samples, where cancer cells are mixed with a proportion of stromal cells. We validate MixHMM and demonstrate its advantages with simulated samples, clinical tumor samples and a dilution series of mixed samples. We have shown that the CNVs of cancer cells in a tumor sample contaminated with up to 80% of stromal cells can be detected accurately using Illumina BeadChip and MixHMM. The MixHMM is available as a Python package provided with some other useful tools at http://genecube.med.yale.edu:8080/MixHMM.

  5. MixHMM: inferring copy number variation and allelic imbalance using SNP arrays and tumor samples mixed with stromal cells.

    Directory of Open Access Journals (Sweden)

    Zongzhi Liu

    Full Text Available BACKGROUND: Genotyping platforms such as single nucleotide polymorphism (SNP arrays are powerful tools to study genomic aberrations in cancer samples. Allele specific information from SNP arrays provides valuable information for interpreting copy number variation (CNV and allelic imbalance including loss-of-heterozygosity (LOH beyond that obtained from the total DNA signal available from array comparative genomic hybridization (aCGH platforms. Several algorithms based on hidden Markov models (HMMs have been designed to detect copy number changes and copy-neutral LOH making use of the allele information on SNP arrays. However heterogeneity in clinical samples, due to stromal contamination and somatic alterations, complicates analysis and interpretation of these data. METHODS: We have developed MixHMM, a novel hidden Markov model using hidden states based on chromosomal structural aberrations. MixHMM allows CNV detection for copy numbers up to 7 and allows more complete and accurate description of other forms of allelic imbalance, such as increased copy number LOH or imbalanced amplifications. MixHMM also incorporates a novel sample mixing model that allows detection of tumor CNV events in heterogeneous tumor samples, where cancer cells are mixed with a proportion of stromal cells. CONCLUSIONS: We validate MixHMM and demonstrate its advantages with simulated samples, clinical tumor samples and a dilution series of mixed samples. We have shown that the CNVs of cancer cells in a tumor sample contaminated with up to 80% of stromal cells can be detected accurately using Illumina BeadChip and MixHMM. AVAILABILITY: The MixHMM is available as a Python package provided with some other useful tools at http://genecube.med.yale.edu:8080/MixHMM.

  6. Mutational profile of KIT and PDGFRA genes in gastrointestinal stromal tumors in Peruvian samples

    Directory of Open Access Journals (Sweden)

    José Buleje

    2015-02-01

    Full Text Available Introduction: Gastrointestinal stromal tumors (GISTs are mesenchymal neoplasms usually caused by somatic mutations in the genes KIT (c-KIT or PDGFRA. Mutation characterization has become an important exam for GIST patients because it is useful in predicting the response to the inhibitors of receptor tyrosine kinase (RTK. Objectives: The aim of this study was to determine the frequency of KIT and PDGFRA mutations in 25 GIST samples collected over two years at two national reference hospitals in Peru. There were 21 samples collected from the Instituto Nacional de Enfermedades Neoplásicas (INEN, national cancer center and 4 samples collected from Hospital A. Loayza. Methods and materials: In this retrospective study, we performed polymerase chain reaction (PCR amplification and deoxyribonucleic acid (DNA sequencing of KIT (exons 9, 11, 13, and 17 and PDGFRA (exons 12 and 18 genes in 20 FFPE (formalin-fixed, paraffin-embedded and 5 frozen GIST samples. Results: We report 21 mutations, including deletions, duplications, and missense, no mutations in 2 samples, and 2 samples with no useful DNA for further analysis. Eighty-six percent of these mutations were located in exon 11 of KIT, and 14 % were located in exon 18 of PDGFRA. Conclusions: Our study identified mutations in 21 out of 25 GIST samples from 2 referential national hospitals in Peru, and the mutation proportion follows a global tendency observed from previous studies (i.e., the majority of samples presented KIT mutations followed by a minor percentage of PDGFRA mutations. This study presents the first mutation data of the KIT and PDGFRA genes from Peruvian individuals with GIST.

  7. Clinicopathologic features, management and outcome of ten cases of gastrointestinal stromal tumors

    Directory of Open Access Journals (Sweden)

    Md. Nazmul Hoque

    2017-07-01

    Full Text Available Background and objectives:Gastrointestinal stromal tumor (GISTs is an uncommon and rare disease in Bangladesh. Our aims were to describe socio-demographic characteristics, clinical presentations, anatomical location, morphological variation, treatment and outcome of GIST in ten cases. Methods:This study included consecutive ten cases of GISTs diagnosed and treated in two tertiary level hospitals in Dhaka, Bangladesh from 2013 to 2016. Patients’ socio-demographic characteristics, clinical presentations, anatomical location, histological types, presence of CD117 markers were determined. Outcome of the treatment by surgical intervention and imatinib mesylate (400mg/day were evalauted. Results: Total 10 patients were included in the study. Among them 6 were male and 4 were female. The age range was 32-74 years. Abdominal pain, haematemesis, melaena, haematochezia and anaemia were the most common presentation. One patient had dysphagia and another had features of subacute intestinal obstruction. Five patients had GIST in the stomach (50%, two had in colon and one in esophagus, duodenum and ileum respectively. CD 117 was positive in 8 cases, majority had spindly type cell with low mitotic figure. Imatinib therapy was given in all the cases except two patients. Disease recurrence in the form liver metastasis was found in two cases and both died. Disease free survival for more than 2 years was observed in 4 cases. Conclusion: Haematemesis and melaena were common presentation of GISTs. Stomach was the most common site for GISTs and majority had spindle type of cells and positive CD117 marker. Surgical intervention and imatinib therapy was found effective. IMC J Med Sci 2017; 11(2: 45-49

  8. Clinical practice and outcomes in advanced gastrointestinal stromal tumor: Experience from an Indian tertiary care center

    Directory of Open Access Journals (Sweden)

    Subhadeep Bose

    2017-01-01

    Full Text Available Background: Management of advanced Gastrointestinal stromal tumors (GIST has been revolutionized with the use of Imatinib guided by mutation analysis. Data from India remains scarce. Materials and Methods: Patients with metastatic GIST who were treated at Department of Gastro-intestinal & Hepaticopancreaticobiliary Oncology Unit at Tata Memorial Hospital, Mumbai between December, 2004 and December 2015 were included in the analysis. Clinical and radiological data was retrieved from stored medical records and charts. Results: A total of 83 patients with metastatic GIST were available for analysis. Median age was 54 years with a 3:1 male predominance. Stomach was the most common site of primary with liver being the most common site of metastasis. c-Kit mutation analysis results were available for 44 patients with exon 11 mutant being the most common mutation. With a median follow up of 33 months, the 10 years estimated progression free and overall survival (OS was 18% and 51% respectively. Overall response rate to first line imatinib was 37.6% and estimated 3 years OS to first line therapy was significantly better for Exon 11 mutated patients (p=0.016. 34 patients received second line therapy in the form of either sunitinib, pazopanib or increased dose imatinib with a clinical benefit rate of 73.5%. C-Kit mutated patients had a better median OS compared to non mutated patients. Conclusions: GIST diagnosed and treated in the Indian subcontinent appears to show improved outcomes. The importance of c-Kit mutation analysis in determining the prognosis and outcomes of patients with advanced GIST is emphasized.

  9. Differentiation of large (≥5 cm) gastrointestinal stromal tumors from benign subepithelial tumors in the stomach: Radiologists’ performance using CT

    Energy Technology Data Exchange (ETDEWEB)

    Choi, Ye Ra [Department of Radiology, Seoul National University Hospital (Korea, Republic of); Kim, Se Hyung, E-mail: shkim7071@gmail.com [Department of Radiology, Seoul National University Hospital (Korea, Republic of); The Institute of Radiation Medicine, Seoul National University Hospital (Korea, Republic of); Kim, Sun-Ah [Department of Radiology, Seoul National University Hospital (Korea, Republic of); Shin, Cheong-il [Department of Radiology, Seoul National University Hospital (Korea, Republic of); The Institute of Radiation Medicine, Seoul National University Hospital (Korea, Republic of); Kim, Hyung Jin; Kim, Seong Ho [Department of Radiology, Seoul National University Hospital (Korea, Republic of); Han, Joon Koo; Choi, Byung Ihn [Department of Radiology, Seoul National University Hospital (Korea, Republic of); The Institute of Radiation Medicine, Seoul National University Hospital (Korea, Republic of)

    2014-02-15

    Purpose: To identify significant CT findings for the differentiation of large (≥5 cm) gastric gastrointestinal stromal tumors (GIST) from benign subepithelial tumors and to assess whether radiologists’ performance in differentiation is improved with knowledge of significant CT criteria. Materials and methods: One-hundred twenty patients with pathologically proven large (≥5 cm) GISTs (n = 99), schwannomas (n = 16), and leiomyomas (n = 5) who underwent CT were enrolled. Two radiologists (A and B) retrospectively reviewed their CT images in consensus for the location, size, degree and pattern of enhancement, contour, growth pattern and the presence of calcification, necrosis, surface ulceration, or enlarged lymph nodes. CT findings considered significant for differentiation were determined using uni- and multivariate statistical analyses. Thereafter, two successive review sessions for the differentiation of GIST from non-GIST were independently performed by two other reviewers (C and D) with different expertise of 2 and 9 years using a 5-point confidence scale. At the first session, reviewers interpreted CT images without knowledge of significant CT findings. At the second session, the results of statistical analyses were provided to the reviewers. To assess improvement in radiologists’ performance, a pairwise comparison of receiver operating curves (ROC) was performed. Results: Heterogeneous enhancement, presence of necrosis, absence of lymph nodes, and mean size of ≥6 cm were found to be significant for differentiating GIST from schwannoma (P < 0.05). Non-cardial location, heterogeneous enhancement, and presence of necrosis were differential CT features of GIST from leiomyoma (P < 0.05). Multivariate analyses indicated that absence of enlarged LNs was the only statistically significant variable for GIST differentiating from schwannoma. The area under the curve of both reviewers obtained using ROC significantly increased from 0.682 and 0.613 to 0.903 and 0

  10. High Stromal Carbonic Anhydrase IX Expression Is Associated With Decreased Survival in p16-Negative Head-and-Neck Tumors

    International Nuclear Information System (INIS)

    Brockton, Nigel; Dort, Joseph; Lau, Harold; Hao, Desiree; Brar, Sony; Klimowicz, Alexander; Petrillo, Stephanie; Diaz, Roman; Doll, Corinne; Magliocco, Anthony

    2011-01-01

    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.

  11. Diagnosis and treatment of small intestinal stromal tumor: an analysis of 45 cases

    Directory of Open Access Journals (Sweden)

    Yan ZENG

    2014-08-01

    Full Text Available Objective To study the clinical features, diagnosis and treatment of small intestinal stromal tumor (SIST. Methods Clinical data of 45 SIST patients admitted to our hospital from July 2007 to December 2013 were analyzed retrospectively. The diagnosis was confirmed pathologically in all the patients. Results The clinical manifestations of SIST were non-specific, and the most common manifestations were as follows: gastrointestinal bleeding in 29 patients (64.4 %, abdominal pain in 15 (33.3% and abdominal mass in 4 (8.9%. The most common predilection sites of SIST were jejunum (n=21, 46.7%, duodenum (n=13, 28.9% and ileum (n=9, 20.0%. The tumor was located at the jejunoileal junction in 2 patients (4.4%. The diagnostic rate of SIST by spiral CT was 73.7% (28/38, and it was the most accurate among all the examinations. Surgical operation was the most effective therapeutic method for SIST. All the 45 patients received surgical treatment, and according to Fletcher's criteria, there were 6 patients (13.3% at very low-risk, 16 (35.6% at low-risk, 8 (17.8% at moderate-risk and 15 (33.3% at highrisk of SIST. The postoperative immunohistochemistry showed that the positive rate of CD117 was 100%, while the positive rate of CD34 was 67.0% (30/45. Imatinib mesylate was helpful for patients who had palliative operation and for preventing postoperative recurrence. Reoperation could prolong the survival of patients who had a local recurrence or distant metastasis. Conclusions  Clinical manifestations of SIST are non-specific, and its early diagnosis is difficult. However, spiral CT has a high diagnostic value for SIST. The surgical operation is the main method for treatment of SIST, and long-time oral imatinib mesylate medication after surgery can attain a better result for a long duration. DOI: 10.11855/j.issn.0577-7402.2014.07.11

  12. Imatinib and gastrointestinal stromal tumor (GIST: a selective targeted therapy Imatinib y tumor del estroma gastrointestinal (GIST: un tratamiento selectivo frente a una diana molecular

    Directory of Open Access Journals (Sweden)

    A. Fernández

    2004-10-01

    Full Text Available Gastrointestinal stromal tumors are the most frequent mesenchymal tumors in the gastrointestinal tract. They originate from the interstitial cells of Cajal and are characterized by an anomalous receptor for a growth factor with tyrosine-kinase activity (c-kit. This anomaly causes a permanent activation of the receptor and uncontrolled cell growth. These tumors show a poor response to traditional chemotherapy drugs, and are thus associated with low survival in cases of advanced disease. Imatinib, a tyrosine kinase inhibitor, is an example of selective targeted oncologic therapy that induces improved survival in these patients. We discuss two cases of metastatic gastrointestinal stromal tumors with a good response to imatinib, and also review the pathophysiology and treatment-related outcome of this type of tumors. We include results from clinical phase-III studies.Los tumores del estroma gastrointestinal son los tumores mesenquimales más frecuentes del tracto digestivo y se originan de las células intersticiales de Cajal. Se caracterizan por presentar un receptor para el factor de crecimiento con actividad tirosin kinasa (c-kit anómalo que condiciona su activación permanente y un crecimiento celular incontrolado. Tienen una baja supervivencia en casos de enfermedad avanzada, con escasa respuesta a los agentes quimioterápicos tradicionales. El imatinib es un fármaco inhibidor de la tirosín kinasa y un ejemplo de terapia oncológica selectiva que condiciona un importante aumento en la supervivencia de estos pacientes. Se presentan 2 casos de enfermedad metastásica con buena respuesta a imatinib, así como una revisión sobre la fisiopatología y evolución en el tratamiento de este tipo de tumores, incluyendo resultados de estudios en fase III.

  13. Predictive value and modeling analysis of MSCT signs in gastrointestinal stromal tumors (GISTs) to pathological risk degree.

    Science.gov (United States)

    Wang, J-K

    2017-03-01

    By analyzing MSCT (multi-slice computed tomography) signs with different risks in gastrointestinal stromal tumors, this paper aimed to discuss the predictive value and modeling analysis of MSCT signs in GISTs (gastrointestinal stromal tumor) to pathological risk degree. 100 cases of primary GISTs with abdominal and pelvic MSCT scan were involved in this study. All MSCT scan findings and enhanced findings were analyzed and compared among cases with different risk degree of pathology. Then GISTs diagnostic model was established by using support vector machine (SVM) algorithm, and its diagnostic value was evaluated as well. All lesions were solitary, among which there were 46 low-risk cases, 24 medium-risk cases and 30 high-risk cases. For all high-risk, medium-risk and low-risk GISTs, there were statistical differences in tumor growth pattern, size, shape, fat space, with or without calcification, ulcer, enhancement method and peritumoral and intratumoral vessels (pvalue at each period (plain scan, arterial phase, venous phase) (p>0.05). The apparent difference lied in plain scan, arterial phase and venous phase for each risk degree. The diagnostic accuracy of SVM diagnostic model established with 10 imaging features as indexes was 70.0%, and it was especially reliable when diagnosing GISTs of high or low risk. Preoperative analysis of MSCT features is clinically significant for its diagnosis of risk degree and prognosis; GISTs diagnostic model established on the basis of SVM possesses high diagnostic value.

  14. Curcumin suppresses crosstalk between colon cancer stem cells and stromal fibroblasts in the tumor microenvironment: potential role of EMT.

    Directory of Open Access Journals (Sweden)

    Constanze Buhrmann

    Full Text Available OBJECTIVE: Interaction of stromal and tumor cells plays a dynamic role in initiating and enhancing carcinogenesis. In this study, we investigated the crosstalk between colorectal cancer (CRC cells with stromal fibroblasts and the anti-cancer effects of curcumin and 5-Fluorouracil (5-FU, especially on cancer stem cell (CSC survival in a 3D-co-culture model that mimics in vivo tumor microenvironment. METHODS: Colon carcinoma cells HCT116 and MRC-5 fibroblasts were co-cultured in a monolayer or high density tumor microenvironment model in vitro with/without curcumin and/or 5-FU. RESULTS: Monolayer tumor microenvironment co-cultures supported intensive crosstalk between cancer cells and fibroblasts and enhanced up-regulation of metastatic active adhesion molecules (β1-integrin, ICAM-1, transforming growth factor-β signaling molecules (TGF-β3, p-Smad2, proliferation associated proteins (cyclin D1, Ki-67 and epithelial-to-mesenchymal transition (EMT factor (vimentin in HCT116 compared with tumor mono-cultures. High density tumor microenvironment co-cultures synergistically increased tumor-promoting factors (NF-κB, MMP-13, TGF-β3, favored CSC survival (characterized by up-regulation of CD133, CD44, ALDH1 and EMT-factors (increased vimentin and Slug, decreased E-cadherin in HCT116 compared with high density HCT116 mono-cultures. Interestingly, this synergistic crosstalk was even more pronounced in the presence of 5-FU, but dramatically decreased in the presence of curcumin, inducing biochemical changes to mesenchymal-epithelial transition (MET, thereby sensitizing CSCs to 5-FU treatment. CONCLUSION: Enrichment of CSCs, remarkable activation of tumor-promoting factors and EMT in high density co-culture highlights that the crosstalk in the tumor microenvironment plays an essential role in tumor development and progression, and this interaction appears to be mediated at least in part by TGF-β and EMT. Modulation of this synergistic crosstalk by

  15. The tumor-stromal ratio as a strong prognosticator for advanced gastric cancer patients: proposal of a new TSNM staging system.

    Science.gov (United States)

    Peng, Chunwei; Liu, Jiuyang; Yang, Guifang; Li, Yan

    2017-08-16

    Insufficient attention is paid to the underlying tumor microenvironment (TME) evolution, that resulting in tumor heterogeneity and driving differences in cancer aggressiveness and treatment outcomes. The morphological evaluation of the proportion of the stroma at the most invasive part of primary tumor (tumor-stromal ratio, TSR) in cancer is gaining momentum as evidence strengthens for the clinical relevance. Tissue samples from the most invasive part of the primary gastric cancer (GC) of 494 patients were analyzed for their TSR, and a new TSNM (tumor-stromal node metastasis) staging system based on patho-biological behaviors was established and assessed. TSR is a new and strong independent prognostic factor for GC patients. The likelihood of tumor invasion is increased significantly for patients in the stromal-high subgroup compared to those in the stromal-low subgroup (P = 0.011). The discrimination ability of TSR was not less than the TNM staging system and was better in patients with stages I and II GC. We integrated the TSR parameter into the TNM staging system and proposed a new TSNM staging system creatively. There were three new subgroups (IC, IIC, IIID). There were four major groups and 10 subgroups in the TSNM system. The difference in overall survival (OS) was statistically significant among all TSNM system (P system has been established to optimize risk stratification for GC. The value of the TSNM staging system should be validated in further prospective study.

  16. When is a GIST not a GIST? A case report of synchronous metastatic gastrointestinal stromal tumor and fibromatosis

    Directory of Open Access Journals (Sweden)

    Desilva Keshani

    2009-01-01

    Full Text Available Abstract Background A number of non-malignant diseases that share similar morphological features as gastrointestinal stromal tumor (GIST have been reported. Co-existence of GIST with these other diseases is rarely recognized or reported. Case presentation We report a case of a 62 year-old man with long-term stable control of metastatic GIST with systemic therapy, presented with an apparent intra-abdominal progression but not supported by imaging with positron emission tomography. Subsequent resection of the intra-abdominal tumor identified a non-malignant fibroid. Conclusion Differentiating localized progression of GIST from other diseases has important prognostic and therapeutic implications. The potential for co-existence of non-malignant soft tissue neoplasm should always be considered.

  17. Gastrointestinal stromal tumor of the vermiform appendix mimicking Meckel’s diverticulum: Case report with literature review

    Science.gov (United States)

    Chun, Jae Min; Lim, Kyoung Hoon

    2016-01-01

    Introduction Gastrointestinal stromal tumors (GISTs) of the appendix are extremely rare. To date, only 15 cases have been reported in the English literature. Here, we present a new case of an appendiceal GIST with appendicitis. Presentation of case A 68-year-old man who complained of right lower abdominal tenderness underwent surgery for a cystic mass mimicking Meckel’s diverticulum. Laparoscopy revealed a mass protruding from the proximal appendix with distal appendicitis. Complete resection with adequate margins was performed. Histology showed a spindle cell GIST without mitotic activity as well as a strong expression of CD117 and CD34. Conclusion Primary appendiceal GIST occur at a very low rate and their symptoms are nonspecific. Accordingly, rare tumors of appendix including GISTs should be considered in the differential diagnosis of atypical symptoms or image findings. PMID:26895113

  18. Current Regulations for the Production of Multipotent Mesenchymal Stromal Cells for Clinical Application.

    Science.gov (United States)

    Slaper-Cortenbach, Ineke C M

    2008-01-01

    SUMMARY: In this review, the appropriate legislation on the expansion of multipotent mesenchymal stromal cells (MSCs) in Europe is described. The collection of cells and the manufacturing of MSCs are being regulated by European Directives (EUDs). Recently, the Regulation on Advanced Therapies Medicinal Products (ATMPs) is being published, which is of importance for the production of MSCs in Europe, and this legislation is not yet ready, but it is in its final stage. MSCs are currently being used in clinical trials, mostly in academic hospitals, for patients suffering from a wide variety of diseases. Companies (small and medium-sized enterprises) are becoming more and more involved in the production of MSCs for human use, and since marketing authorisation is the scope of the Regulation it was decided to install a Committee on Advanced Therapies (CAT) within European Medicines Agency (EMEA). This CAT will formulate a draft opinion on quality, safety and efficacy of ATMPs and will have an advisory and scientific role for the Committee for Medicinal Products for human use. The aim of this review is to outline the current legislation which is important for the manufacturing of MSCs.

  19. Therapeutic Efficacy Assessment of CK6, a Monoclonal KIT Antibody, in a Panel of Gastrointestinal Stromal Tumor Xenograft Models

    Directory of Open Access Journals (Sweden)

    Thomas Van Looy

    2015-04-01

    Full Text Available We evaluated the efficacy of CK6, a KIT monoclonal antibody, in a panel of human gastrointestinal stromal tumor (GIST xenograft models. Nude mice were bilaterally transplanted with human GIST xenografts (four patient derived and two cell line derived, treated for 3 weeks, and grouped as follows: control (untreated; CK6 (40 mg/kg, 3× weekly; imatinib (50 mg/kg, twice daily; sunitinib (40 mg/kg, once daily; imatinib + CK6; sunitinib + CK6 (same doses and schedules as in the single-agent treatments. Tumor volume assessment, Western blot analysis, and histopathology were used for evaluation of efficacy. Statistical analysis was performed using Mann-Whitney U (MWU and Wilcoxon matched-pairs tests. CK6 as a single agent only reduced tumor growth rate in the UZLX-GIST3 model (P = .053, MWU compared to control, while in none of the other GIST models an effect on tumor growth rate was observed. CK6 did not result in significant anti-proliferative or pro-apoptotic effects in any of the GIST models, and moreover, CK6 did not induce a remarkable inhibition of KIT activation. Furthermore, no synergistic effect of combining CK6 with tyrosine kinase inhibitors (TKIs was observed. Conversely, in certain GIST xenografts, anti-tumor effects seemed to be inferior under combination treatment compared to single-agent TKI treatment. In the GIST xenografts tested, the anti-tumor efficacy of CK6 was limited. No synergy was observed on combination of CK6 with TKIs in these GIST models. Our findings highlight the importance of using relevant in vivo human tumor xenograft models in the preclinical assessment of drug combination strategies.

  20. Multiple malignant extragastrointestinal stromal tumors of the greater omentum and results of immunohistochemistry and mutation analysis: A case report

    Science.gov (United States)

    Kim, Jong-Han; Boo, Yoon-Jung; Jung, Cheol-Woong; Park, Sung-Soo; Kim, Seung-Joo; Mok, Young-Jae; Kim, Sang-Dae; Chae, Yang-Suk; Kim, Chong-Suk

    2007-01-01

    To report an extragastrointestinal stromal tumor (EGIST) that occurs outside the gastrointestinal tract and shows unique clinicopathologic and immunohistochemical features. In our case, we experienced multiple soft tissue tumors that originate primarily in the greater omentum, and in immunohistochemical analysis, the tumors showed features that correspond to malignant EGIST. Two large omental masses measured 15 cm x 10 cm and 5 cm × 4 cm sized and several small ovoid fragments were attached to small intestine, mesentery and peritoneum. On histologic findings, the masses were separated from small bowel serosa and had high mitotic count (115/50 HPFs). In the results of immunohistochemical stains, the tumor showed CD117 (c-kit) positive reactivity and high Ki-67 labeling index. On mutation analysis, the c-kit gene mutation was found in the juxtamembrane domain (exon 11) and it was heterozygote. Platelet-derived growth factor receptor (PDGFR) gene mutation was also found in the juxtamemembrane (exon 12) and it was polymorphism. From above findings, we proposed that there may be several mutational pathways to malignant EGIST, so further investigations could be needed to approach this unfavorable disease entity. PMID:17659683

  1. Current Concepts on Gastric Carcinoid Tumors

    Directory of Open Access Journals (Sweden)

    George C. Nikou

    2012-01-01

    Full Text Available Gastric carcinoid tumors (GCs are rare lesions representing less than 10% of carcinoid tumors and less than 1% of all stomach neoplasms. There are three distinct types of gastric carcinoids; type I includes the vast majority (70–85% of these neoplasms that are closely linked to chronic atrophic gastritis. Type II which accounts for 5–10 %, is associated with Zollinger-Ellison syndrome and often occurs in the context of multiple endocrine neoplasia type 1. Type III, finally, represents 15–25% of gastric carcinoids and is characterized by a far more aggressive course. The optimal clinical approach to GCs remains to be elucidated, depending upon type, size, and number of carcinoids. While there is universal agreement about the surgical treatment of type III GCs, current options for type I and II include simple surveillance, endoscopic polypectomy, surgical excision associated with or without surgical antrectomy, or total gastrectomy. Moreover, the introduction of somatostatin analogues could represent another therapeutic option.

  2. Inactivation of Patched1 in mice leads to development of gastrointestinal stromal-like tumors that express Pdgfrα but not kit

    NARCIS (Netherlands)

    Pelczar, Penelope; Zibat, Arne; van Dop, Willemijn A.; Heijmans, Jarom; Bleckmann, Annalen; Gruber, Wolfgang; Nitzki, Frauke; Uhmann, Anja; Guijarro, Maria V.; Hernando, Eva; Dittmann, Kai; Wienands, Jürgen; Dressel, Ralf; Wojnowski, Leszek; Binder, Claudia; Taguchi, Takahiro; Beissbarth, Tim; Hogendoorn, Pancras C. W.; Antonescu, Cristina R.; Rubin, Brian P.; Schulz-Schaeffer, Walter; Aberger, Fritz; van den Brink, Gijs R.; Hahn, Heidi

    2013-01-01

    A fraction of gastrointestinal stromal tumor (GIST) cells overexpress the platelet-derived growth factor receptor (PDGFR)A, although most overexpress KIT. It is not known if this is because these receptor tyrosine kinases have complementary oncogenic potential, or because of heterogeneity in the

  3. Cellular schwannoma arising from the gastric wall misdiagnosed as a gastric stromal tumor: A case report.

    Science.gov (United States)

    Wang, Guangyao; Chen, Ping; Zong, Liang; Shi, Lei; Zhao, Wei

    2014-02-01

    Cellular schwannomas have been previously described at almost every anatomic location of the human body, but reports in the gastric wall are rare. The current study presents a rare case of cellular schwannoma originating from the gastric wall. Computed tomography revealed a 5.6×5.3×4.0-cm 3 solid mass located in the posterior wall of the stomach. Open laparotomy confirmed its mesenchymal origin. Microscopically, the tissue was composed of spindle-shaped and fascicularly-arranged cells, but mitotic figures were rare. Immunohistochemical staining showed that the tumor was negative for cluster of differentiation (CD)117, CD34, smooth muscle actin and desmin, but positive for S-100 and Ki67. The patient presented no evidence of recurrence and metastasis during follow-up. Gastric cellular schwannomas may be diagnosed by clinical characteristics, histological observations and immunohistochemical markers.

  4. Does the Loss of Stromal Caveolin-1 Remodel the Tumor Microenvironment by Activating Src-Mediated PEAK1 and PI3K Pathways

    Science.gov (United States)

    2017-11-01

    patients harbor AKT1 and that AKT1 kinase activity is sustained in these particles, nominating them as active signaling platforms. Consistently, active...INTRODUCTION It has gradually become clear that the tumor stromal environment , also called the tumor microenvironment (TME), plays a crucial role in the...in the context of prostate cancer, EV populations isolated from human patients harbor AKT1 and that AKT1 kinase activity is sustained in these

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

    Science.gov (United States)

    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).

  6. Combination of Imatinib Mesylate and AKT Inhibitor Provides Synergistic Effects in Preclinical Study of Gastrointestinal Stromal Tumor.

    Science.gov (United States)

    Zook, Phillip; Pathak, Harsh B; Belinsky, Martin G; Gersz, Lawrence; Devarajan, Karthik; Zhou, Yan; Godwin, Andrew K; von Mehren, Margaret; Rink, Lori

    2017-01-01

    Gastrointestinal stromal tumors (GIST) generally harbor activating mutations in the receptor tyrosine kinase KIT or in the related platelet-derived growth factor receptor alpha (PDGFRA). GIST treated with imatinib mesylate or second-line therapies that target mutant forms of these receptors generally escape disease control and progress over time. Inhibiting additional molecular targets may provide more substantial disease control. Recent studies have implicated the PI3K/AKT pathway in the survival of imatinib mesylate-resistant GIST cell lines and tumors. Here, we performed in vitro and in vivo studies evaluating the novel combination of imatinib mesylate with the AKT inhibitor MK-2206 in GIST. Whole-transcriptome sequencing (WTS) of xenografts was performed to explore the molecular aspects of tumor response to this novel combination and to potentially identify additional therapeutic targets in GIST. This drug combination demonstrated significant synergistic effects in a panel of imatinib mesylate-sensitive and -resistant GIST cell lines. Furthermore, combination therapy provided significantly greater efficacy, as measured by tumor response and animal survival, in imatinib mesylate-sensitive GIST xenografts as compared with treatment with imatinib mesylate or MK-2206 alone. WTS implicated two neural genes, brain expressed X-linked 1 and neuronal pentraxin I, whose expression was significantly upregulated in combination-treated tumors compared with tumors treated with the two monotherapies. These studies provide strong preclinical justification for combining imatinib mesylate with an AKT inhibitor as a front-line therapy in GIST. In addition, the WTS implicated the BCL-2/BAX/BAD apoptotic pathway as a potential mechanism for this enhanced combination effect. Clin Cancer Res; 23(1); 171-80. ©2016 AACR. ©2016 American Association for Cancer Research.

  7. Surgical treatment and prognostic analysis for gastrointestinal stromal tumors (GISTs of the small intestine: before the era of imatinib mesylate

    Directory of Open Access Journals (Sweden)

    Jan Yi-Yin

    2006-10-01

    Full Text Available Abstract Background Gastrointestinal stromal tumors (GISTs, the most common type of mesenchymal tumors of the gastrointestinal (GI tract, demonstrate positive kit staining. We report our surgical experience with 100 small intestine GIST patients and identify predictors for long-term disease-free survival (DFS and overall survival (OS to clarify the difference between high- and low-risk patients. Methods The clinicopathologic and follow-up records of 100 small intestine GIST patients who were treated at Chung Gung Memorial Hospital between 1983 and 2002 were retrospectively reviewed. Clinical and pathological factors were assessed for long-term DFS and OS by using a univariate log-rank test and a multivariate Cox proportional hazard model. Results The patients included 52 men and 48 women. Their ages ranged from 27 to 82 years. Among the 85 patients who underwent curative resection, 44 (51.8% developed disease recurrence (liver metastasis was the most common form of recurrence. The follow-up period ranged from 5 to 202 months (median: 33.2 months. The 1-, 3-, and 5-year DFS and OS rates were 85.2%, 53.8%, and 43.7%, and 91.5%, 66.6%, and 50.5%, respectively. Using multivariate analysis, it was found that high tumor cellularity, mitotic count >5/50 high-power field, and a Ki-67 index ≧10% were three independent factors that were inversely associated with DFS. However, absence of tumor perforation, mitotic count Conclusion Tumors with low cellularity, low mitotic count, and low Ki-67 index, which indicate low risk, predict a more favorable DFS for small intestine GIST patients undergoing curative resection. Absence of tumor perforation with low mitotic count and low cellularity, which indicates low risk, can predict long-term OS for small intestine GIST patients who have undergone curative resection.

  8. Gastrointestinal Stromal Tumors (GIST) of the Stomach: Retrospective Experience with Surgical Resection at the National Cancer Institute

    International Nuclear Information System (INIS)

    NAGUIB, Sh.F.; ZAGHLOUL, A.S.; El MARAKBY, H.

    2008-01-01

    Gastric Gist's account for more than half of all gastrointestinal stromal tumors and represent less than 5% of all gastric tumors. The peak age for harboring Gist of the stomach is around 60 years and a slight male preponderance is reported. These tumors are identified by expression of CD117 or CD34 antigen. Symptoms at presentation usually include bleeding, ab¬dominal pain or abdominal mass. Endoscopically, they typically appear as a submucosal mass with or without ulceration and on CT scans an extra gastric mass is usually seen. Complete surgical resection provides the only chance for cure, with only l-2 cm free margins needed. However, local recurrence and/or metastases supervene in almost half the patients treated with surgery alone, even when no gross residual is left. Thereby imatinib mesylate was advocated as an adjuvant to surgery, which appears to have improved disease-free and overall survival. Aim of the Work: The aim of this work was to assess clinico-pathological features of gastrointestinal stromal tumors (GIST) of the stomach and to appraise the results of treatment by surgery in patients treated at the National Cancer Institute (NCI) of Cairo between January 2002 and December 2007. Patients and Methods: Nineteen patients with histologically and immuno-histochemically proven GIST of the stomach were treated by surgery at the NCI during the 6-year study period. Preoperative assessment included detailed history, clinical examination, full laboratory tests, endoscopy, abdominal ultrasound and CT. General medical assessment included chest X-ray, ECG and echocardiography. Results: The patients' age ranged from 26 to 77 years with a median of 51 years. Obvious male/female preponderance was noticed (68.4% to 31.6%). Tumors were located at the upper 1/3 in 42.1%, at the middle 1/3 in 31.6% and at the lower 1/3 in 26.3%. The most common clinical presentation was related to bleeding (hematemesis, melena or anaemia) and was seen in 63.2%. No tumors were

  9. Mixed epithelial and stromal tumor of the kidney (MEST) simulating an upper tract TCC.

    Science.gov (United States)

    Sountoulides, Petros; Koptsis, Michail; Metaxa, Linda; Theodosiou, Alexandros; Kikidakis, Dimitrios; Filintatzi, Chrysa; Paschalidis, Konstantinos

    2012-02-01

    We present a rare and interesting case of a mixed epithelial and stromal tumour (MEST) of the kidney. The case is unique as it involves a male patient with no history of hormonal therapy presenting with a filling defect in the renal collecting system and positive urine cytology. The patient was diagnosed with transitional cell carcinoma of the renal pelvis and subjected to nephroureterectomy, which revealed a solid tumour arising from the lower calyces and extending into the renal pelvis and upper ureter. Pathology revealed a MEST. The patient was disease-free at the 6-month follow-up.

  10. Mesenchymal stromal cells for cardiovascular repair: current status and future challenges

    DEFF Research Database (Denmark)

    Mathiasen, Anders Bruun; Haack-Sørensen, Mandana; Kastrup, Jens

    2009-01-01

    of treatments in patients with heart failure, the 1-year mortality is still approximately 20% after the diagnosis has been established. Treatment with stem cells with the potential to regenerate the damaged myocardium is a relatively new approach. Mesenchymal stromal cells are a promising source of stem cells...... studies are promising, but there are still many unanswered questions. In this review, we explore present preclinical and clinical knowledge regarding the use of stem cells in cardiovascular regenerative medicine, with special focus on mesenchymal stromal cells. We take a closer look at sources of stem...

  11. Imatinib mesylate induces responses in patients with liver metastases from gastrointestinal stromal tumor failing intra-arterial hepatic chemotherapy

    Directory of Open Access Journals (Sweden)

    Fiorentini Giammaria

    2006-01-01

    Full Text Available Background: Imatinib mesylate represents a real major paradigm shift in cancer therapy, targeting the specific molecular abnormalities, crucial in the etiology of tumor. Intra-arterial hepatic chemotherapy (IAHC followed by embolization, has been considered an interesting palliative option for patients with liver metastases from gastrointestinal stromal tumor (GIST, due to the typically hypervascular pattern of the tumor. Aims: We report our experience with IAHC followed by Imatinib mesylate, in order to show the superiority of the specific molecular approach in liver metastases from GIST. Materials and Methods: Three patients (pts with pretreated massive liver metastases from GIST, received IAHC with Epirubicin 50 mg/mq, every 3 weeks for 6 cycles. At the evidence of progression, they received Imatinib mesylate. Results: We observed progressive diseases in all cases. In 1998, one patient underwent Thalidomide at 150 mg orally, every day for 4 months, with evidence of stable disease and clinical improvement. In 2001, two patients received Imatinib mesylate at 400 mg orally, every day, with evidence of partial response lasting 18+ months and 16 months. One of them had grade 3 neutropenia, with suspension of therapy for 3 weeks. Conclusion: No patient treated with IAHC, reported objective responses, but two of them obtained partial response after the assumption of Imatinib mesylate and one showed temporary stabilization with thalidomide. Imatinib mesylate represents a new opportunity in GIST therapy, targeting the specific molecular alteration. It seems to be superior to conventional intra arterial hepatic chemotherapy.

  12. The administration of multipotent stromal cells at precancerous stage precludes tumor growth and epithelial dedifferentiation of oral squamous cell carcinoma.

    Science.gov (United States)

    Bruna, Flavia; Arango-Rodríguez, Martha; Plaza, Anita; Espinoza, Iris; Conget, Paulette

    2017-01-01

    Multipotent stromal cells (MSCs) are envisioned as a powerful therapeutic tool. As they home into tumors, secrete trophic and vasculogenic factors, and suppress immune response their role in carcinogenesis is a matter of controversy. Worldwide oral squamous cell carcinoma (OSCC) is the fifth most common epithelial cancer. Our aim was to determine whether MSC administration at precancerous stage modifies the natural progression of OSCC. OSCC was induced in Syrian hamsters by topical application of DMBA in the buccal pouch. At papilloma stage, the vehicle or 3×10 6 allogenic bone marrow-derived MSCs were locally administered. Four weeks later, the lesions were studied according to: volume, stratification (histology), proliferation (Ki-67), apoptosis (Caspase 3 cleaved), vasculature (ASMA), inflammation (Leukocyte infiltrate), differentiation (CK1 and CK4) and gene expression profile (mRNA). Tumors found in individuals that received MSCs were smaller than those presented in the vehicle group (87±80 versus 54±62mm 3 , p<0.05). The rate of proliferation was two times lower and the apoptosis was 2.5 times higher in lesions treated with MSCs than in untreated ones. While the laters presented dedifferentiated cells, the former maintained differentiated cells (cytokeratin and gene expression profile similar to normal tissue). Thus, MSC administration at papilloma stage precludes tumor growth and epithelial dedifferentiation of OSCC. Copyright © 2016. Published by Elsevier B.V.

  13. Robot-Assisted Excision of a Pararectal Gastrointestinal Stromal Tumor in a Patient with Previous Ileal Neobladder

    Directory of Open Access Journals (Sweden)

    A. Ploumidis

    2014-01-01

    Full Text Available Gastrointestinal stromal tumors (GISTs are the most frequent mesenchymal tumors of the gastrointestinal tract with surgical resection remaining the cornerstone of therapy. Pararectal lesions are considered to be technically difficult and pose in some cases a challenge. We report, to the best of our knowledge, the first robotic-assisted pararectal GIST excision. A 43-year-old man was referred to our center with pararectal GIST recurrence, despite treatment with targeted therapy. Eleven years ago, he underwent extensive abdominal surgery including cystoprostatectomy with ileal neobladder diversion due to GIST resection in the rectoprostatic space. Robot-assisted surgical resection was successfully performed without the need for temporary colostomy. The postoperative course of the patient was uneventful, and the pathology report confirmed a GIST recurrence with negative surgical margins and pelvic lymph nodes free of any tumor. Robotic-assisted pelvic surgery can be extended to incorporate excision of pararectal GISTs, as a safe, less invasive surgical alternative with promising oncological results and minimal injury to adjacent structures.

  14. Malignant stromal tumor of the stomach with giant cystic liver metastases prior to treatment with imatinib mesylate.

    Science.gov (United States)

    Colović, Radoje; Micev, Marjan; Matić, Slavko; Colović, Natasa; Grubor, Nikica; Atkinson, Henry Dushan

    2013-02-01

    Gastrointestinal stromal tumors (GISTs) are rare and account for 0.1%-3% of all gastrointestinal neoplasms. GISTs are most commonly located in the stomach (60%) and 20%-25% are malignant, with metastases involving the peritoneum or the liver. Cystic liver metastases are extremely rare. Only two previous cases of patients with cystic liver metastases, prior to treatment with imatinib mesylate, have been described so far. We reported a 52-year-old woman presented with a history of abdominal fullness and discomfort. Clinical examination revealed two palpable masses, first in the right upper abdomen and second left to the umbilicus. Examinations revealed 4 cystic metastases in the liver, 3 in the right lobe (including a huge one measuring 20.5 x 16 cm), and 1 in the left lobe, together with a primary tumor on the greater curvature of the stomach. Gastric tumor was removed with a Billroth II gastrectomy. Partial excision of the largest liver metastasis was performed for histopathology. Immunohistochemistry confirmed the diagnosis of a GIST in both tissue samples. After an uneventful recovery the patient was commenced on imatinib mesylate therapy. The patient remainsed symptom-free at 24 months follow-up. This was the third reported case of gastric GIST with giant cystic liver metastases present prior to treatment with imatinib mesylate. Although extremely rare, GISTs may present with cystic liver metastases prior to treatment with imatinib mesylate, and should be considered in the differential diagnoses of patients with liver cysts of uncertain aetiology.

  15. The heat shock protein 90 inhibitor IPI-504 induces KIT degradation, tumor shrinkage, and cell proliferation arrest in xenograft models of gastrointestinal stromal tumors.

    Science.gov (United States)

    Floris, Giuseppe; Debiec-Rychter, Maria; Wozniak, Agnieszka; Stefan, Cristiana; Normant, Emmanuel; Faa, Gavino; Machiels, Kathleen; Vanleeuw, Ulla; Sciot, Raf; Schöffski, Patrick

    2011-10-01

    The activity of the receptor tyrosine kinase KIT is crucial for gastrointestinal stromal tumor (GIST) growth and survival. Imatinib and sunitinib are very effective in advanced GIST, but have no curative potential. The observation that heat shock protein 90 (HSP90) inhibition results in KIT degradation prompted us to assess the efficacy of the HSP90 inhibitor retaspimycin hydrochloride (IPI-504) alone or in combination with imatinib or sunitinib in two GIST xenografts with distinctive KIT mutations. Nude mice were grafted with human GIST carrying KIT exon 13 (GIST-882; n = 59) or exon 11 (GIST-PSW; n = 44) mutations and dosed with imatinib (50 mg/kg twice daily), sunitinib (40 mg/kg once daily), IPI-504 (100 mg/kg 3 times per week), IPI-504 + imatinib, or IPI-504 + sunitinib. We evaluated tumor volume, proliferation and apoptosis, KIT expression and activation, as well as adverse events during treatment. Treatment with IPI-504 alone resulted in tumor regression, proliferation arrest, and induction of tumor necrosis. We documented downregulation of KIT and its signaling cascade in IPI-504-treated animals. Treatment effects were enhanced by combining IPI-504 with imatinib or sunitinib. On histologic examination, liver damage was frequently observed in animals exposed to combination treatments. In conclusion, IPI-504 shows consistent antitumor activity and induces KIT downregulation in GIST, as a single agent, and is more potent in combination with imatinib or sunitinib. The sequence of drug administration in the combination arms warrants further studies.

  16. Tumores del estroma gastrointestinal (GIST: factores pronósticos de supervivencia tras citorreducción R0 Gastrointestinal stromal tumors (GIST: factors predictive of survival after R0-cytoreduction

    Directory of Open Access Journals (Sweden)

    J. M. Sánchez Hidalgo

    2007-12-01

    . Demographic, anatomical, clinical, pathological, and immunohistochemical variables were analyzed from a specific database. Survival and multivariate analyses were developed using Kaplan-Meier and multiple Cox regression models, respectively. Results: five-year overall survival was 77% with a mean survival of 52 months. Risk of malignant behaviour according to Fletcher's classification and tumor size higher than 10 cm had a significantly negative influence on overall survival in the univariate analysis (p 50% and currently alive. Conclusions: the poliferative Ki-67 index could represent an excellent predictive factor for survival in patients with c-kit-positive stromal gastrointestinal tumors. Confirmation and an adequate cut-off level should be the main objectives for future prospective studies, mostly focused on the appropriate selection of optimal candidates to imatinib-mesylate-based treatment.

  17. Primary localized rectal/pararectal gastrointestinal stromal tumors: results of surgical and multimodal therapy from the French Sarcoma group

    International Nuclear Information System (INIS)

    Huynh, Thanh-Khoa; Montemurro, Michael; Bompas, Emmanuelle; Rios, Maria; Isambert, Nicolas; Cupissol, Didier; Blay, Jean-Yves; Duffaud, Florence; Meeus, Pierre; Cassier, Philippe; Bouché, Olivier; Lardière-Deguelte, Sophie; Adenis, Antoine; André, Thierry; Mancini, Julien; Collard, Olivier

    2014-01-01

    Rectal and pararectal gastrointestinal stromal tumors (GISTs) are rare. The optimal management strategy for primary localized GISTs remains poorly defined. We conducted a retrospective analysis of 41 patients with localized rectal or pararectal GISTs treated between 1991 and 2011 in 13 French Sarcoma Group centers. Of 12 patients who received preoperative imatinib therapy for a median duration of 7 (2-12) months, 8 experienced a partial response, 3 had stable disease, and 1 had a complete response. Thirty and 11 patients underwent function-sparing conservative surgery and abdominoperineal resection, respectively. Tumor resections were mostly R0 and R1 in 35 patients. Tumor rupture occurred in 12 patients. Eleven patients received postoperative imatinib with a median follow-up of 59 (2.4-186) months. The median time to disease relapse was 36 (9.8-62) months. The 5-year overall survival rate was 86.5%. Twenty patients developed local recurrence after surgery alone, two developed recurrence after resection combined with preoperative and/or postoperative imatinib, and eight developed metastases. In univariate analysis, the mitotic index (≤5) and tumor size (≤5 cm) were associated with a significantly decreased risk of local relapse. Perioperative imatinib was associated with a significantly reduced risk of overall relapse and local relapse. Perioperative imatinib therapy was associated with improved disease-free survival. Preoperative imatinib was effective. Tumor shrinkage has a clear benefit for local excision in terms of feasibility and function preservation. Given the complexity of rectal GISTs, referral of patients with this rare disease to expert centers to undergo a multidisciplinary approach is recommended

  18. Assessing tumor vascularization as a potential biomarker of imatinib resistance in gastrointestinal stromal tumors by dynamic contrast-enhanced magnetic resonance imaging.

    Science.gov (United States)

    Consolino, Lorena; Longo, Dario Livio; Sciortino, Marianna; Dastrù, Walter; Cabodi, Sara; Giovenzana, Giovanni Battista; Aime, Silvio

    2017-07-01

    Most metastatic gastrointestinal stromal tumors (GISTs) develop resistance to the first-line imatinib treatment. Recently, increased vessel density and angiogenic markers were reported in GISTs with a poor prognosis, suggesting that angiogenesis is implicated in GIST tumor progression and resistance. The purpose of this study was to investigate the relationship between tumor vasculature and imatinib resistance in different GIST mouse models using a noninvasive magnetic resonance imaging (MRI) functional approach. Immunodeficient mice (n = 8 for each cell line) were grafted with imatinib-sensitive (GIST882 and GIST-T1) and imatinib-resistant (GIST430) human cell lines. Dynamic contrast-enhanced MRI (DCE-MRI) was performed on GIST xenografts to quantify tumor vessel permeability (K trans ) and vascular volume fraction (v p ). Microvessel density (MVD), permeability (mean dextran density, MDD), and angiogenic markers were evaluated by immunofluorescence and western blot assays. Dynamic contrast-enhanced magnetic resonance imaging showed significantly increased vessel density (P < 0.0001) and permeability (P = 0.0002) in imatinib-resistant tumors compared to imatinib-sensitive ones. Strong positive correlations were observed between MRI estimates, K trans and v p , and their related ex vivo values, MVD (r = 0.78 for K trans and r = 0.82 for v p ) and MDD (r = 0.77 for K trans and r = 0.94 for v p ). In addition, higher expression of vascular endothelial growth factor receptors (VEGFR2 and VEFGR3) was seen in GIST430. Dynamic contrast-enhanced magnetic resonance imaging highlighted marked differences in tumor vasculature and microenvironment properties between imatinib-resistant and imatinib-sensitive GISTs, as also confirmed by ex vivo assays. These results provide new insights into the role that DCE-MRI could play in GIST characterization and response to GIST treatment. Validation studies are needed to confirm these findings.

  19. Targeted Brain Tumor Treatment: Current Perspectives

    Directory of Open Access Journals (Sweden)

    Ningaraj N.S

    2007-01-01

    Full Text Available Brain tumor is associated with poor prognosis. The treatment option is severely limited for a patient with brain tumor, despite great advances in understanding the etiology and molecular biology of brain tumors that have lead to breakthroughs in developing pharmaceutical strategies, and ongoing NCI/Pharma-sponsored clinical trials. We reviewed the literature on molecular targeted agents in preclinical and clinical studies in brain tumor for the past decade, and observed that the molecular targeting in brain tumors is complex. This is because no single gene or protein can be affected by single molecular agent, requiring the use of combination molecular therapy with cytotoxic agents. In this review, we briefly discuss the potential molecular targets, and the challenges of targeted brain tumor treatment. For example, glial tumors are associated with over-expression of calcium-dependent potassium (KCa channels, and high grade glioma express specific KCa channel gene (gBK splice variants, and mutant epidermal growth factor receptors (EGFRvIII. These specific genes are promising targets for molecular targeted treatment in brain tumors. In addition, drugs like Avastin and Gleevec target the molecular targets such as vascular endothelial cell growth factor receptor, platelet-derived growth factor receptors, and BRC-ABL/Akt. Recent discovery of non-coding RNA, specifically microRNAs could be used as potential targeted drugs. Finally, we discuss the role of anti-cancer drug delivery to brain tumors by breaching the blood-brain tumor barrier. This non-invasive strategy is particularly useful as novel molecules and humanized monoclonal antibodies that target receptor tyrosine kinase receptors are rapidly being developed.

  20. Targeted Brain Tumor Treatment-Current Perspectives

    Directory of Open Access Journals (Sweden)

    N.S. Ningaraj

    2007-01-01

    Full Text Available Brain tumor is associated with poor prognosis. The treatment option is severely limited for a patient with brain tumor, despite great advances in understanding the etiology and molecular biology of brain tumors that have lead to breakthroughs in developing pharmaceutical strategies, and ongoing NCI/Pharma-sponsored clinical trials. We reviewed the literature on molecular targeted agents in preclinical and clinical studies in brain tumor for the past decade, and observed that the molecular targeting in brain tumors is complex. This is because no single gene or protein can be affected by single molecular agent, requiring the use of combination molecular therapy with cytotoxic agents. In this review, we briefly discuss the potential molecular targets, and the challenges of targeted brain tumor treatment. For example, glial tumors are associated with over-expression of calcium-dependent potassium (K Ca channels, and high grade glioma express specific K Ca channel gene (gBK splice variants, and mutant epidermal growth factor receptors (EGFRvIII. These specific genes are promising targets for molecular targeted treatment in brain tumors. In addition, drugs like Avastin and Gleevec target the molecular targets such as vascular endothelial cell growth factor receptor, platelet-derived growth factor receptors, and BRC-ABL/Akt. Recent discovery of non-coding RNA, specifically microRNAs could be used as potential targeted drugs. Finally, we discuss the role of anti-cancer drug delivery to brain tumors by breaching the blood-brain tumor barrier. This non-invasive strategy is particularly useful as novel molecules and humanized monoclonal antibodies that target receptor tyrosine kinase receptors are rapidly being developed.

  1. Mechanical properties of the tumor stromal microenvironment probedin vitroandex vivobyin situ-calibrated optical trap-based active microrheology.

    Science.gov (United States)

    Staunton, Jack R; Vieira, Wilfred; Fung, King Leung; Lake, Ross; Devine, Alexus; Tanner, Kandice

    2016-09-01

    One of the hallmarks of the malignant transformation of epithelial tissue is the modulation of stromal components of the microenvironment. In particular, aberrant extracellular matrix (ECM) remodeling and stiffening enhances tumor growth and survival and promotes metastasis. Type I collagen is one of the major ECM components. It serves as a scaffold protein in the stroma contributing to the tissue's mechanical properties, imparting tensile strength and rigidity to tissues such as those of the skin, tendons, and lungs. Here we investigate the effects of intrinsic spatial heterogeneities due to fibrillar architecture, pore size and ligand density on the microscale and bulk mechanical properties of the ECM. Type I collagen hydrogels with topologies tuned by polymerization temperature and concentration to mimic physico-chemical properties of a normal tissue and tumor microenvironment were measured by in situ -calibrated A ctive M icrorheology by O ptical T rapping revealing significantly different microscale complex shear moduli at Hz-kHz frequencies and two orders of magnitude of strain amplitude that we compared to data from bulk rheology measurements. Access to higher frequencies enabled observation of transitions from elastic to viscous behavior that occur at ~200Hz to 2750Hz, which largely was dependent on tissue architecture well outside the dynamic range of instrument acquisition possible with SAOS bulk rheology. We determined that mouse melanoma tumors and human breast tumors displayed complex moduli ~5-1000 Pa, increasing with frequency and displaying a nonlinear stress-strain response. Thus, we show the feasibility of a mechanical biopsy in efforts to provide a diagnostic tool to aid in the design of therapeutics complementary to those based on standard histopathology.

  2. Activating mutations in c-KIT and PDGFRalpha are exclusively found in gastrointestinal stromal tumors and not in other tumors overexpressing these imatinib mesylate target genes.

    Science.gov (United States)

    Burger, Herman; den Bakker, Michael A; Kros, Johan M; van Tol, Hans; de Bruin, Alex M; Oosterhuis, Wolter; van den Ingh, Harry F G M; van der Harst, Erwin; de Schipper, Hans P; Wiemer, Erik A C; Nooter, Kees

    2005-11-01

    Previous studies have shown that Imatinib mesylate (Gleevec), a selective tyrosine kinase inhibitor of c-KIT and platelet-derived growth factor receptors (PDGFR), is highly effective in c-KIT/CD117-positive gastrointestinal stromal tumors (GIST), especially in those having activating mutations in c-kit exon 11. In addition, gain-of-function mutations in the juxtamembrane domain (exon 12) and the kinase activation loop (exon 18) of PDGFRalpha were found in GISTs. Importantly, the presence and type of these mutually exclusive c-KIT or PDGFRalpha mutations were found to be associated with the response to imatinib. Here, we examined the prevalence of c-kit exon 11 and PDGFRalpha exons 12 and 18 mutations in other tumor types known to express these tyrosine kinase receptors in order to explore which other cancer types may potentially benefit from imatinib treatment. We determined the mutational status of these commonly mutated exons by direct sequencing in 11 different tumor types (in total: 215 unrelated cases), including GIST, chordoma, and various distinct tumors of lung, brain and its coverings, and skin cancer. Of the 579 exons examined (211 c-kit exon 11, 192 PDGFRalpha exon 12, 142 PDGFRalpha exon18, 17 PDGFRbeta exon 12 and 17 PDGFRbeta exon 18), only 12 (all GIST) harbored mutations (10 c-kit exon 11 and 2 PDGFRalpha exon18). From these data we conclude that activating c-KIT and PDGFR mutations are sporadic in human cancers known to overexpress these tyrosine kinase receptor genes and suggest that, except in GIST, this overexpression is not correlated with activating mutations. The latter may imply that these wild-type c-KIT and PDGFR tumor types will probably not benefit from imatinib treatment.

  3. Small bud of probable gastrointestinal stromal tumor within a laparoscopically-resected gastric schwannoma.

    Science.gov (United States)

    Cho, Haruhiko; Watanabe, Takafumi; Aoyama, Toru; Hayashi, Tsutomu; Yamada, Takanobu; Ogata, Takashi; Yoshikawa, Takaki; Tsuburaya, Akira; Sekiguchi, Hironobu; Nakamura, Yoshiyasu; Sakuma, Yuji; Kameda, Yoichi; Miyagi, Yohei

    2012-06-01

    Submucosal tumors (SMTs) of the gastrointestinal (GI) tract can be potentially difficulty to diagnose pathologically. We report a case of a gastric SMT that was resected by laparoscopic partial gastrectomy. Although the initial histological and immunohistochemical examinations considered the tumor as a schwannoma, mRNA-based KIT genotyping indicated that the tumor included cells with KIT gene expression, and that a small number of cells carried a deletion mutation in exon 11. Additional histopathological investigations revealed small aggregates of enlarged spindle to epithelioid cells, which were positive for KIT, CD34 and DOG1, and negative for S-100, scattered among the S-100-positive schwannoma cells. We consider that the cells carrying the KIT gene mutation are microscopic buds of a gastrointestinal stroma tumor (GIST), and to the best of our knowledge, this is the first report of probable GIST tissues identified in a schwannoma. Our observations raised the significance of genotyping for diagnosis of GI tract SMTs.

  4. Hemorragia digestiva provocada por tumor estromal gastrointestinal avançado de duodeno Gastrointestinal hemorrhage caused by advanced duodenal gastrointestinal stromal tumor

    Directory of Open Access Journals (Sweden)

    Ruy Jorge Cruz Jr

    2007-12-01

    Full Text Available INTRODUÇÃO: O tumor estromal gastrointestinal (GIST é neoplasia pouco freqüente, sendo rara a combinação de acometimento duodenal e hemorragia digestiva, por isso apresenta-se este relato. RELATO DO CASO: Homem de 64 anos admitido com quadro de dor abdominal, melena e tumoração palpável em epigástrio e hipocôndrio esquerdo, sendo notado um tumor de paredes espessadas e conteúdo cístico na tomografia computadorizada de abdome, em topografia de cauda pancreática. Encontrado na laparotomia de urgência tumor em quarta porção duodenal com invasão de cólon em ângulo esplênico, sendo realizada ressecção em bloco do duodeno acometido, segmento de cólon transverso e descendente, com boa evolução pós-operatória. Diagnosticado por imunoistoquímica GIST de duodeno com invasão de parede colônica, sendo o tratamento complementado com mesilato de imatinib. CONCLUSÃO: A hemorragia digestiva é uma das possíveis complicações do GIST. Apenas o tratamento cirúrgico precoce é capaz de prevenir as graves complicações do choque hemorrágico.BACKGROUND: Gastrointestinal stromal tumor (GIST represents an uncommon form of neoplasm. The combination of duodenal GIST and gastrointestinal bleeding consist of a rare presentation for such tumors. AIM: To report duodenal GIST case complicated by gastrointestinal bleeding. CASE REPORT: A 64-year-old male was admitted presenting abdominal pain, melena and a palpable mass in epigastrium and left upper abdomem regions. CT scan reveled a thick wall tumor containing cystic content in the pancreatic tail topography. At emergency laparotomy, a tumor in the fourth portion of the duodenum presenting colonic invasion in splenic flexure was found. En-bloc resection of the tumor was carried out, included the fourth portion of the duodenum and the transverse and descending colon, without postoperative complications. Immunohistochemical staining of the resected specimen confirmed the diagnosis of

  5. The outcome and predictive factors of sunitinib therapy in advanced gastrointestinal stromal tumors (GIST after imatinib failure - one institution study

    Directory of Open Access Journals (Sweden)

    Rutkowski Piotr

    2012-03-01

    Full Text Available Abstract Background Gastrointestinal stromal tumors (GIST mutational status is recognized factor related to the results of tyrosine kinase inhibitors therapy such as imatinib (IM or sunitinib (SU. Arterial hypertension (AH is common adverse event related to SU, reported as predictive factor in renal cell carcinoma. The aim of the study was to analyze the outcomes and factors predicting results of SU therapy in inoperable/metastatic CD117(+ GIST patients after IM failure. Methods We identified 137 consecutive patients with advanced inoperable/metastatic GIST treated in one center with SU (2nd line treatment. Median follow-up time was 23 months. Additionally, in 39 patients there were analyzed selected constitutive single nucleotide polymorphisms (SNPs of VEGFA and VEGFR2 genes. Results One year progression-free survival (PFS; calculated from the start of SU rate was 42% and median PFS was 43 weeks. The estimated overall survival (OS, calculated both from start of SU or IM was 74 weeks and 51 months, respectively. One-year PFS was 65% (median 74 weeks in 55 patients with AH vs. 22% (median 17 weeks in patients without AH. Patients with primary tumors carrying mutations in KIT exon 9 or wild-type had substantially better 1-year PFS (68% and 57%; median 65.5 and 50.5 weeks, respectively than patients having tumors with KIT exon 11 or PDGFRA mutations (34% and 15%; median 36.8 and 9 weeks, respectively. We identified two independent factors with significant impact on PFS and OS in univariate and multivariate analysis: primary tumor genotype and presence of AH. The most common adverse events during therapy were: fatigue, AH, hypothyroidism, hand and foot syndrome, mucositis, skin reactions, dyspepsia, and diarrhea. Two deaths were assessed as related to tumor rupture caused by reaction to SU therapy. The presence of C-allele in rs833061 and the T-allele in rs3025039 polymorphism of VEGFA were associated with significantly higher risk of hypothyroidism

  6. Spontaneous formation of tumorigenic hybrids between breast cancer and multipotent stromal cells is a source of tumor heterogeneity.

    Science.gov (United States)

    Rappa, Germana; Mercapide, Javier; Lorico, Aurelio

    2012-06-01

    Breast cancer progression involves cancer cell heterogeneity, with generation of invasive/metastatic breast cancer cells within populations of nonmetastatic cells of the primary tumor. Sequential genetic mutations, epithelial-to-mesenchymal transition, interaction with local stroma, and formation of hybrids between cancer cells and normal bone marrow-derived cells have been advocated as tumor progression mechanisms. We report herein the spontaneous in vitro formation of heterotypic hybrids between human bone marrow-derived multipotent stromal cells (MSCs) and two different breast carcinoma cell lines, MDA-MB-231 (MDA) and MA11. Hybrids showed predominantly mesenchymal morphological characteristics, mixed gene expression profiles, and increased DNA ploidy. Both MA11 and MDA hybrids were tumorigenic in immunodeficient mice, and some MDA hybrids had an increased metastatic capacity. Both in culture and as xenografts, hybrids underwent DNA ploidy reduction and morphological reversal to breast carcinoma-like morphological characteristics, while maintaining a mixed breast cancer-mesenchymal expression profile. Analysis of coding single-nucleotide polymorphisms by RNA sequencing revealed genetic contributions from both parental partners to hybrid tumors and metastasis. Because MSCs migrate and localize to breast carcinoma, our findings indicate that formation of MSC-breast cancer cell hybrids is a potential mechanism of the generation of invasive/metastatic breast cancer cells. Our findings reconcile the fusion theory of cancer progression with the common observation that breast cancer metastases are generally aneuploid, but not tetraploid, and are histopathologically similar to the primary neoplasm. Copyright © 2012 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  7. SDHA loss of function mutations in a subset of young adult wild-type gastrointestinal stromal tumors

    International Nuclear Information System (INIS)

    Italiano, Antoine; Chen, Chun-Liang; Sung, Yun-Shao; Singer, Samuel; DeMatteo, Ronald P; LaQuaglia, Michael P; Besmer, Peter; Socci, Nicholas; Antonescu, Cristina R

    2012-01-01

    A subset of KIT/PDGFRA wild-type gastrointestinal stromal tumors (WT GIST) have been associated with alteration of the succinate dehydrogenase (SDH) complex II function. A recent report identified four non-syndromic, KIT/PDGFRA WT GIST harboring compound heterozygous or homozygous mutations in SDHA encoding the main subunit of the SDH complex II. Next generation sequencing was applied on five pediatric and one young adult WT GIST, by whole exome capture and SOLiD 3-plus system sequencing. The putative mutations were first confirmed by Sanger sequencing and then screened on a larger panel of 11 pediatric and young adult WT GIST, including 5 in the context of Carney triad. A germline p.Arg31X nonsense SDHA mutation was identified in one of the six cases tested by SOLiD platform. An additional p.D38V missense mutation in SDHA exon 2 was identified by Sanger sequencing in the extended KIT/PDGFRA WT GIST patients cohort. Western blotting showed loss of SDHA expression in the two cases harboring SDHA mutations, while expression being retained in the other WT GIST tumors. Results were further confirmed by immunohistochemistry for both SDHA and SDHB, which showed a concurrent loss of expression of both proteins in SDHA-mutant lesions, while the remaining WT tumors showed only loss of SDHB expression. Germline and/or somatic aberrations of SDHA occur in a small subset of KIT/PDGFRA WT GISTs, outside the Carney’s triad and are associated with loss of both SDHA and SDHB protein expression. Mutations of the SDH complex II are more particularly associated with KIT/PDGFRA WT GIST occurring in young adults. Although pediatric GIST consistently display alterations of SDHB protein expression, further molecular studies are needed to identify the crucial genes involved in their tumorigenesis

  8. CCR 20th Anniversary Commentary: A Genetic Mechanism of Imatinib Resistance in Gastrointestinal Stromal Tumor-Where Are We a Decade Later?

    Science.gov (United States)

    Antonescu, Cristina R; DeMatteo, Ronald P

    2015-08-01

    In the June 1, 2005, issue of Clinical Cancer Research, Antonescu and colleagues defined second-site KIT mutations in gastrointestinal stromal tumor (GIST) as the leading mechanism of acquired resistance to imatinib. Secondary mutations were detectable mainly in KIT exon 11 mutant GISTs after prolonged initial clinical responses. These findings played a critical role in designing the next generation of tyrosine kinase inhibitors. ©2015 American Association for Cancer Research.

  9. Epithelial-stromal interaction 1 (EPSTI1) substitutes for peritumoral fibroblasts in the tumor microenvironment

    DEFF Research Database (Denmark)

    De Neergaard, Michala; Kim, Jiyoung; Villadsen, René

    2010-01-01

    of human breast cancer cells and activated breast myofibroblasts. Here we describe the first immunolocalization of EPSTI1 in normal and cancerous breast tissue, and we provide evidence for a role of this molecule in the regulation of tumor cell properties and epithelial-mesenchymal transition. In general...... cell line and silenced endogenous EPSTI1 by RNA interference in another. Irrespective of the experimental approach, EPSTI1 expression led to an increase in tumorsphere formation-a property associated with breast stem/progenitor cells. Most remarkably, we show that EPSTI1, by conveying spread of tumor...

  10. Massive Intra-Abdominal Imatinib-Resistant Gastrointestinal Stromal Tumor in a 21-Year-Old Male

    Directory of Open Access Journals (Sweden)

    Ann Falor

    2013-01-01

    Full Text Available Gastrointestinal stromal tumors (GISTs in adolescence are far less common than adult GISTs and have varied GIST genotypes that present diagnostic and therapeutic challenges. Here, we discuss a 21-year-old male with diagnosis of unresectable, imatinib-resistant GIST. At initial evaluation, a neoadjuvant treatment approach was recommended. As such, the patient received imatinib over the course of one year. Unfortunately, the GIST increased in size, and a subsequent attempt at surgical resection was aborted fearing infiltration of major vascular structures. The patient was then referred to our institution, at which time imatinib therapy was discontinued. Surgical intervention was again considered and the patient underwent successful resection of massive intra-abdominal GIST with total gastrectomy and Roux-en-Y esophagojejunostomy. Since pediatric GISTs are typically resistant to imatinib, we performed genotype analysis of the operative specimen that revealed KIT mutations associated with imatinib sensitivity and resistance. Given the sequencing data and operative findings, the patient was started postoperatively on sunitinib. This case illustrates the importance of understanding both adult and pediatric GISTs when implementing appropriate treatment regimens. Since the genotype of GISTs dictates phenotypic behavior, mutational analysis is an important component of care especially for adolescents whose disease may mirror the pediatric or adult population.

  11. Imatinib-associated bilateral gynecomastia and unilateral testicular hydrocele in male patient with metastatic gastrointestinal stromal tumor: a literature review.

    Science.gov (United States)

    Tanriverdi, Ozgur; Unubol, Mustafa; Taskin, Fisun; Meydan, Nezih; Sargin, Gokhan; Guney, Engin; Barutca, Sabri

    2012-06-01

    Imatinib mesylate is a drug that has been approved for treatment of advanced gastrointestinal stromal tumors (GISTs) and patients with leukemia such as chronic myeloid or Philadelphia chromosome-positive acute lymphoblastic. Although it has been described only in one patient with testicular hydrocele and gynecomastia in the literature, several cases of male gynecomastia have been reported with the use of imatinib mesylate in chronic myeloid leukemia (GML). Generally, male mastoplasia resolves after discontinuation of imatinib treatment. We report a 73-year-old male with metastatic GISTs who developed gynecomastia and unilateral testicular hydrocele while receiving imatinib mesylate. Nine months after commencing imatinib treatment, gynecomastia and testicular hydrocele were determined. Hormone analyses requested showed serum testosterone levels below and serum estrogen levels above normal limits. During the first month after discontinuing imatinib mesylate treatment, serum testosterone level was normal and there was a partial regression in gynecomastia and testicular hydrocele. To our knowledge, this is the second report of male gynecomastia following imatinib mesylate treatment of a patient with GIST. In conclusion, male patients who are to receive treatment with imatinib mesylate may be monitored for serum testosterone levels and for other reproductive hormone profiles before initiation of the treatment and their breasts may be examined during follow-up visits.

  12. Development of nano radiopharmaceutical based on Bevacizumab labelled with Technetium-99m for early diagnosis of gastrointestinal stromal tumor; Desenvolvimento de nanorradiofarmaco a base de Bevacizumabe marcado com tecnecio-99m para diagnostico precoce do tumor estromal gastrointestinal

    Energy Technology Data Exchange (ETDEWEB)

    Braga, Thais Ligiero

    2015-06-01

    The development of new radiopharmaceuticals is an essential activity to improve nuclear medicine, and essential for the early and effective diagnosis of oncological diseases. Among the various possibilities current research in the world, the radiopharmaceuticals to chemotherapeutic base may be the most effective in detecting tumors, particularly Gastrointestinal Stromal Tumor (GIST), the Metastatic Renal Cell Carcinoma and neuroendocrine pancreatic tumors. However, difficulties in directing, as well as adhesion of the radiopharmaceutical in the desired location, are currently the main problems in the early detection and treatment of some of these tumors. Advances in the field of nanotechnology, particularly in recent years, indicate significant contribution to overcoming these obstacles, particularly in the implementation of molecular barriers as well as the functionalization of the nanoparticles, thereby improving targeting by the use of surface nucleotides, and the increased adhesion, which facilitates the release of the drug and therefore increases the chances of early diagnosis and more effective treatment. This study aimed to the production, characterization and evaluation of cytotoxicity, as well as in vivo biodistribution test Bevacizumab nanoparticles labeled with Technetium-99m radionuclide for detection of type GIST tumors. Bevacizumab was encapsulated in the form of nanoparticles by the emulsification method using double poly-acetic acid and polyvinyl alcohol polymers (PLA / PVA) at a concentration of 2% of the monoclonal antibody. The characterization of the nanoparticles was performed by the technique of scanning electron microscopy (SEM). The cytotoxicity assessment was performed by XTT assay with various cell lines of solid tumor cells. The labeling with technetium-99m was done by the direct method, and its yield determined by paper chromatography using paper Whatmam 1 as the stationary phase and acetone as mobile phase. In the biodistribution study

  13. Multiple non-metastatic gastrointestinal stromal tumors: Differential features Tumores del estroma gastrointestinal múltiples no metastásicos: Aspectos diferenciales

    Directory of Open Access Journals (Sweden)

    M. Díaz Delgado

    2010-08-01

    Full Text Available Introduction: gastrointestinal stromal tumors (GISTs are specific, generally KIT (CD117-positive, mesenchymal tumors of the digestive tract displaying KIT or PDGFRA gene mutations. Clinically, they tend to present as solitary tumors of the intestinal wall; more rarely, multiple tumors may occur in one or more organs. Objective: to review the morphological, immunohistochemical and molecular features of multiple, non-metastatic forms of GIST. Sources: review of the literature on Medline, and authors' own experience. Conclusions: multiples GISTs may occur in three different contexts: as spontaneous lesions (in both adults and children; due to familial GIST syndrome (autosomal dominant inheritance; or in association with specific syndromes (e.g. Carney's triad, Carney-Stratakis syndrome, type I neurofibromatosis. Outside these contexts, the existence of multiple GISTs is deemed to be the result of tumor metastasis, and therefore indicative of advanced-stage disease. Clinicians need to be aware of these variants, whose prognosis and treatment differ.Introducción: los tumores del estroma gastrointestinal (GIST son neoplasias mesenquimales del tubo digestivo que generalmente expresan el receptor KIT (CD117 y muestran mutaciones en los genes KIT o PDGFRA. Aunque la forma de presentación clínica habitual es como una neoplasia mural solitaria, excepcionalmente pueden presentarse formas múltiples en el mismo o diferente órgano. Objetivo: revisar las características morfológicas, inmunohistoquímicas y moleculares de las formas de GIST múltiples no metastásicos. Fuentes: revisión de la literatura en Medline y la propia experiencia. Conclusiones: los GIST múltiples pueden presentarse en tres contextos diferentes: lesiones espontáneas (del adulto o de la edad infantil; síndrome familiar propio (transmitido con herencia autosómica dominante; y lesiones asociadas a síndromes específicos (tríada de Carney, síndrome de Carney-Stratakis, y

  14. The Novel HSP90 inhibitor, IPI-493, is highly effective in human gastrostrointestinal stromal tumor xenografts carrying heterogeneous KIT mutations.

    Science.gov (United States)

    Floris, Giuseppe; Sciot, Raf; Wozniak, Agnieszka; Van Looy, Thomas; Wellens, Jasmien; Faa, Gavino; Normant, Emmanuel; Debiec-Rychter, Maria; Schöffski, Patrick

    2011-09-01

    KIT activity is crucial for gastrointestinal stromal tumors (GIST). Imatinib (IMA) and sunitinib (SUN) are very effective KIT-inhibitors in patients with advanced GIST but have no curative potential. We evaluated the efficacy of the novel HSP90 inhibitor IPI-493 alone, or in combination with IMA or SUN in GIST xenografts with KIT mutations. Nude mice (n = 98) were grafted bilaterally with human GIST carrying KIT exon 11 (GIST-PSW), KIT exon 9 (GIST-BOE), or double, KIT imatinib-sensitive exon 11 and imatinib-resistant exon 17 mutations (GIST-48). Mice were divided into six treatment groups and dosed orally for 15 days as follows: (i) control group, sterile water; (ii) IMA alone; (iii) SUN alone; (iv) IPI-493 alone; (v) IPI-493+IMA; and (vi) IPI-493+SUN. Treatment with IPI-493 resulted in tumor growth stabilization, variable proliferation arrest, induction of apoptosis and necrosis, and downregulation of KIT and its signaling cascade, especially in the GIST-BOE model. Significant reduction of vessel density was observed with IPI-493 treatment, and was equal to SUN treatment in GIST-PSW and GIST-BOE xenografts. IPI-493 treatment effects were enhanced in combination with TKIs, especially with IPI-493+SUN. In our hands, IPI-493 showed dose-dependent liver damages. When administered as a single agent in a xenograft model, the HSP90 inhibitor IPI-493 has consistent antitumor activity and induces KIT downregulation in GISTs with heterogeneous KIT mutations. IPI-493 synergizes with TKIs that are commonly used for the treatment of advanced or IMA-resistant GIST. The antitumor response of IPI-493 is particularly enhanced in combination with SUN. ©2011 AACR.

  15. SV40 Infection of Mesenchymal Stromal Cells From Wharton's Jelly Drives the Production of Inflammatory and Tumoral Mediators.

    Science.gov (United States)

    Cason, Carolina; Campisciano, Giuseppina; Zanotta, Nunzia; Valencic, Erica; Delbue, Serena; Bella, Ramona; Comar, Manola

    2017-11-01

    The Mesenchymal Stromal Cells from umbilical cord Wharton's jelly (WJSCs) are a source of cells with high potentiality for the treatment of human immunological disorders. Footprints of the oncogenic viruses Simian Virus 40 (SV40) and JC Virus (JCPyV) have been recently detected in human WJSCs specimens. The aim of this study is to evaluate if WJSCs can be efficiently infected by these Polyomaviruses and if they can potentially exert tumoral activity. Cell culture experiments indicated that WJSCs could sustain both SV40 and JCPyV infections. A transient and lytic replication was observed for JCPyV, while SV40 persistently infected WJSCs over a long period of time, releasing a viral progeny at low titer without evident cytopathic effect (CPE). Considering the association between SV40 and human tumors and the reported ability of the oncogenic viruses to drive the host innate immune response to cell transformation, the expression profile of a large panel of immune mediators was evaluated in supernatants by the Bioplex platform. RANTES, IL-3, MIG, and IL-12p40, involved in chronic inflammation, cells differentiation, and transformation, were constantly measured at high concentration comparing to control. These findings represent a new aspect of SV40 biological activity in the humans, highlighting its interaction with specific host cellular pathways. In view of these results, it seems to be increasingly urgent to consider Polyomaviruses in the management of WJSCs for their safely use as promising therapeutic source. J. Cell. Physiol. 232: 3060-3066, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  16. Bone Marrow Suppression by c-Kit Blockade Enhances Tumor Growth of Colorectal Metastases through the Action of Stromal Cell-Derived Factor-1

    Directory of Open Access Journals (Sweden)

    Kathrin Rupertus

    2012-01-01

    Full Text Available Background. Mobilization of c-Kit+ hematopoietic cells (HCs contributes to tumor vascularization. Whereas survival and proliferation of HCs are regulated by binding of the stem cell factor to its receptor c-Kit, migration of HCs is directed by stromal cell-derived factor (SDF-1. Therefore, targeting migration of HCs provides a promising new strategy of anti-tumor therapy. Methods. BALB/c mice (=16 were pretreated with an anti-c-Kit antibody followed by implantation of CT26.WT-GFP colorectal cancer cells into dorsal skinfold chambers. Animals (=8 additionally received a neutralizing anti-SDF-1 antibody. Animals (=8 treated with a control antibody served as controls. Investigations were performed using intravital fluorescence microscopy, immunohistochemistry, flow cytometry and western blot analysis. Results. Blockade of c-Kit significantly enhanced tumor cell engraftment compared to controls due to stimulation of tumor cell proliferation and invasion without markedly affecting tumor vascularization. C-Kit blockade significantly increased VEGF and CXCR4 expression within the growing tumors. Neutralization of SDF-1 completely antagonized this anti-c-Kit-associated tumor growth by suppression of tumor neovascularization, inhibition of tumor cell proliferation and reduction of muscular infiltration. Conclusion. Our study indicates that bone marrow suppression via anti-c-Kit pretreatment enhances tumor cell engraftment of colorectal metastases due to interaction with the SDF-1/CXCR4 pathway which is involved in HC-mediated tumor angiogenesis.

  17. Mutations in Exons 9 and 13 of KIT Gene Are Rare Events in Gastrointestinal Stromal Tumors : A Study of 200 Cases

    OpenAIRE

    Lasota, Jerzy; Wozniak, Agnieszka; Sarlomo-Rikala, Maarit; Rys, Janusz; Kordek, Radzislaw; Nassar, Aziza; Sobin, Leslie H.; Miettinen, Markku

    2000-01-01

    Gastrointestinal stromal tumors (GISTs), the most common mesenchymal tumors of the gastrointestinal tract, typically express the KIT protein. Activating mutations in the juxtamembrane domain (exon 11) of the c-kit gene have been shown in a subset of GISTs. These mutations lead into ligand-independent activation of the tyrosine kinase of c-kit, and have a transforming effect in vitro. Several groups have studied the clinical implication of the c-kit mutation status of exon 11 in GISTs and a po...

  18. The Impact of Epithelial-Stromal Interactions on Human Breast Tumor Heterogeneity

    Science.gov (United States)

    2014-10-01

    pathways associated with poor outcome in TN tumors, we will uncover mechanisms for co‐ evolution, biomarkers and potential  therapeutic   targets.   Our...position  the  tumor  microenvironment  for  therapeutic   intervention.    This  project  also  promises  the  "next  generation"  of  signatures...500  including  matched  samples  and  reduction  mammoplasties )  tissue  samples  obtained  from  surgeries  conducted at the McGill University

  19. A New Paradigm for Ovarian Sex Cord-Stromal Tumor Development

    Science.gov (United States)

    2016-05-01

    cell tumors in these mice. In the ovary culture system , SB- 505124 seemed to improve follicle development in TGFBR1-gCA ovaries. Therefore, sustained...treated with H2O2 and blocked with 5% non- immune serum, and incubated with primary and secondary antibodies and Avidin/Biotin Complex (ABC; Vector...collagenase digestion of P12 ovaries (Eppig & O’Brien 1996). While OGCs retrieved from the control mice were morphologically normal and similar in size

  20. A New Paradigm for Ovarian Sex Cord-Stromal Tumor Development

    Science.gov (United States)

    2017-05-01

    versus controls. Interestingly, a number of genes are associated with folliculogenesis and oogenesis. Further studies will be focused on exploiting the...ovaries and antibodies directed to inhibin alpha (INHA), forkhead box L2 (FOXL2), and DEAD (Asp-Glu-Ala-Asp) box polypeptide 4 (DDX4...not develop ovarian tumors, making them unsuitable for the proposed experiment. Thus, we made a minor modification of the experimental approach to

  1. Single cell dual adherent-suspension co-culture micro-environment for studying tumor-stromal interactions with functionally selected cancer stem-like cells.

    Science.gov (United States)

    Chen, Yu-Chih; Zhang, Zhixiong; Fouladdel, Shamileh; Deol, Yadwinder; Ingram, Patrick N; McDermott, Sean P; Azizi, Ebrahim; Wicha, Max S; Yoon, Euisik

    2016-08-07

    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

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

    Energy Technology Data Exchange (ETDEWEB)

    Berglund, Erik, E-mail: erik.berglund@ki.se [Endocrine and Sarcoma Surgery Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm (Sweden); Department of Breast and Endocrine Surgery, Karolinska University Hospital, Stockholm (Sweden); Akcakaya, Pinar [Department of Oncology-Pathology, Karolinska Institutet, Cancer Center Karolinska, Stockholm (Sweden); Berglund, David [Section for Transplantation Surgery, Department of Surgical Sciences, Uppsala University Hospital, Uppsala (Sweden); Karlsson, Fredrik [Endocrine and Sarcoma Surgery Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm (Sweden); Department of Breast and Endocrine Surgery, Karolinska University Hospital, Stockholm (Sweden); Vukojević, Vladana [Department of Clinical Neuroscience, Karolinska Institutet, Stockholm (Sweden); Lee, Linkiat [Department of Oncology-Pathology, Karolinska Institutet, Cancer Center Karolinska, Stockholm (Sweden); Bogdanović, Darko [Endocrine and Sarcoma Surgery Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm (Sweden); Lui, Weng-Onn; Larsson, Catharina [Department of Oncology-Pathology, Karolinska Institutet, Cancer Center Karolinska, Stockholm (Sweden); Zedenius, Jan [Endocrine and Sarcoma Surgery Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm (Sweden); Department of Breast and Endocrine Surgery, Karolinska University Hospital, Stockholm (Sweden); Fröbom, Robin [Endocrine and Sarcoma Surgery Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm (Sweden); Bränström, Robert [Endocrine and Sarcoma Surgery Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm (Sweden); Department of Breast and Endocrine Surgery, Karolinska University Hospital, Stockholm (Sweden)

    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.

  3. Anti-angiogenesis therapy based on the bone marrow-derived stromal cells genetically engineered to express sFlt-1 in mouse tumor model

    Directory of Open Access Journals (Sweden)

    Chen X-C

    2008-10-01

    Full Text Available Abstract Background Bone marrow-derived stromal cells (BMSCs are important for development, tissue cell replenishment, and wound healing in physiological and pathological conditions. BMSCs were found to preferably reach sites undergoing the process of cell proliferation, such as wound and tumor, suggesting that BMSCs may be used as a vehicle for gene therapy of tumor. Methods Mouse BMSCs were loaded with recombinant adenoviruses which express soluble Vascular Endothelial Growth Factor Receptor-1 (sFlt-1. The anti-angiogenesis of sFlt-1 in BMSCs was determined using endothelial cells proliferation inhibition assay and alginate encapsulation assay. The anti-tumor effects of BMSCs expressing sFlt-1 through tail-vein infusion were evaluated in two mouse tumor metastases models. Results BMSCs genetically modified with Adv-GFP-sFlt-1 could effectively express and secret sFlt-1. BMSCs loaded with sFlt-1 gene could preferentially home to tumor loci and decrease lung metastases and prolong lifespan in mouse tumor model through inducing anti-angiogenesis and apoptosis in tumors. Conclusion We demonstrated that BMSCs might be employed as a promising vehicle for tumor gene therapy which can effectively not only improve the concentration of anticancer therapeutics in tumors, but also modify the tumor microenvironment.

  4. The Role of ADAM9 in Tumor-Stromal Interactions in Breast Cancer

    Science.gov (United States)

    2010-04-01

    supplemented with 10% fetal bovine serum. MCF10A cells were maintained in DMEM modified with 5% equine serum, 20ng/ml EGF, 10ug/ml insulin, 100ng/ml cholera... wound healing response (26). Tumors are sites of chronic wounding , and cancer cells adapt to the wound by increasing cell migration and angiogenesis...involved in wound healing. We find that while ADAM9-S promotes cell migration via its metalloprotease activity (Fig. 2A), ADAM9-L functions as a

  5. Effect of water-soluble P-chitosan and S-chitosan on human primary osteoblasts and giant cell tumor of bone stromal cells

    Energy Technology Data Exchange (ETDEWEB)

    Tang, T; Zhang, G; PY Lau, Carol; Zheng, L Z; Xie, X H; Wang, X L; Patrick, Y; Qin, L; Kumta, Shekhar M [Department of Orthopaedics and Traumatology, Chinese University of Hong Kong (Hong Kong); Wang, X H; He, K, E-mail: kumta@cuhk.edu.hk [Department of Mechanical Engineering, Institute of Bio-manufacturing Engineering, Tsinghua University, Beijing (China)

    2011-02-15

    Water-soluble phosphorylated chitosan (P-chitosan) and disodium (1 {yields} 4)-2-deoxy-2-sulfoamino-{beta}-D-glucopyranuronan (S-chitosan) are two chemically modified chitosans. In this study, we found that P-chitosan significantly promotes cell proliferation of both human primary osteoblasts (OBs) and the OB like stromal cell component of the giant cell tumor of bone (GCTB) cells at the concentration from 125 to 1000 {mu}g ml{sup -1} at all time points of 1, 3, 5 and 7 days after treatment. Further investigation of the osteogenic effect of the P-chitosan suggested that it regulates the levels of osteoclastogenic factors, receptor activator of nuclear factor kappa B ligand and osteoprotegerin expression. An interesting finding is that S-chitosan at lower concentration (100 {mu}g ml{sup -1}) stimulates cell proliferation while a higher dose (1000 {mu}g ml{sup -1}) of S-chitosan inhibits it. The inhibitory effect of S-chitosan on human primary GCT stromal cells was greater than that of OBs (p < 0.05). Taken together, our findings elucidated the osteogenic effect of P-chitosan and the varying effects of S-chitosan on the proliferation of human primary OBs and GCT stromal cells and provided us the rationale for the construction of novel bone repair biomaterials with the dual properties of bone induction and bone tumor inhibition.

  6. A signature of epithelial-mesenchymal plasticity and stromal activation in primary tumor modulates late recurrence in breast cancer independent of disease subtype.

    Science.gov (United States)

    Cheng, Qing; Chang, Jeffrey T; Gwin, William R; Zhu, Jun; Ambs, Stefan; Geradts, Joseph; Lyerly, H Kim

    2014-07-25

    Despite improvements in adjuvant therapy, late systemic recurrences remain a lethal consequence of both early- and late-stage breast cancer. A delayed recurrence is thought to arise from a state of tumor dormancy, but the mechanisms that govern tumor dormancy remain poorly understood. To address the features of breast tumors associated with late recurrence, but not confounded by variations in systemic treatment, we compiled breast tumor gene expression data from 4,767 patients and established a discovery cohort consisting of 743 lymph node-negative patients who did not receive systemic neoadjuvant or adjuvant therapy. We interrogated the gene expression profiles of the 743 tumors and identified gene expression patterns that were associated with early and late disease recurrence among these patients. We applied this classification to a subset of 46 patients for whom expression data from microdissected tumor epithelium and stroma was available, and identified a distinct gene signature in the stroma and also a corresponding tumor epithelium signature that predicted disease recurrence in the discovery cohort. This tumor epithelium signature was then validated as a predictor for late disease recurrence in the entire cohort of 4,767 patients. We identified a novel 51-gene signature from microdissected tumor epithelium associated with late disease recurrence in breast cancer independent of the molecular disease subtype. This signature correlated with gene expression alterations in the adjacent tumor stroma and describes a process of epithelial to mesenchymal transition (EMT) and tumor-stroma interactions. Our findings suggest that an EMT-related gene signature in the tumor epithelium is related to both stromal activation and escape from disease dormancy in breast cancer. The presence of a late recurrence gene signature in the primary tumor also suggests that intrinsic features of this tumor regulate the transition of disseminated tumor cells into a dormant phenotype with

  7. Immunization of stromal cell targeting fibroblast activation protein providing immunotherapy to breast cancer mouse model.

    Science.gov (United States)

    Meng, Mingyao; Wang, Wenju; Yan, Jun; Tan, Jing; Liao, Liwei; Shi, Jianlin; Wei, Chuanyu; Xie, Yanhua; Jin, Xingfang; Yang, Li; Jin, Qing; Zhu, Huirong; Tan, Weiwei; Yang, Fang; Hou, Zongliu

    2016-08-01

    Unlike heterogeneous tumor cells, cancer-associated fibroblasts (CAF) are genetically more stable which serve as a reliable target for tumor immunotherapy. Fibroblast activation protein (FAP) which is restrictively expressed in tumor cells and CAF in vivo and plays a prominent role in tumor initiation, progression, and metastasis can function as a tumor rejection antigen. In the current study, we have constructed artificial FAP(+) stromal cells which mimicked the FAP(+) CAF in vivo. We immunized a breast cancer mouse model with FAP(+) stromal cells to perform immunotherapy against FAP(+) cells in the tumor microenvironment. By forced expression of FAP, we have obtained FAP(+) stromal cells whose phenotype was CD11b(+)/CD34(+)/Sca-1(+)/FSP-1(+)/MHC class I(+). Interestingly, proliferation capacity of the fibroblasts was significantly enhanced by FAP. In the breast cancer-bearing mouse model, vaccination with FAP(+) stromal cells has significantly inhibited the growth of allograft tumor and reduced lung metastasis indeed. Depletion of T cell assays has suggested that both CD4(+) and CD8(+) T cells were involved in the tumor cytotoxic immune response. Furthermore, tumor tissue from FAP-immunized mice revealed that targeting FAP(+) CAF has induced apoptosis and decreased collagen type I and CD31 expression in the tumor microenvironment. These results implicated that immunization with FAP(+) stromal cells led to the disruption of the tumor microenvironment. Our study may provide a novel strategy for immunotherapy of a broad range of cancer.

  8. Molecules involved in epithelial-mesenchymal transition and epithelial-stromal interaction in phyllodes tumors: implications for histologic grade and prognosis.

    Science.gov (United States)

    Kwon, Ji Eun; Jung, Woo-Hee; Koo, Ja Seung

    2012-06-01

    The aim of this study was to investigate the expression of molecules associated with epithelial-mesenchymal transition (EMT) and epithelial-stromal interactions (ESI) and to evaluate their roles in phyllodes tumors (PTs). Tissue microarrays (TMAs) were constructed from 207 PT specimens (157 benign, 34 borderline and 16 malignant). The presence of EMT-related markers including N-cadherin, Twist, TGF-beta, HMGA2, S100A4 and Ezrin as well as ESI-related molecules such as SDF1 and CXCR4 among the TMAs was assessed immunohistochemically. Immunohistochemical results were analyzed in terms of clinicopathologic parameters. For higher grade PTs, expressions of Twist (p grade PTs. Further, high expression of Twist in the stromal component was correlated with poorer prognoses.

  9. Efficacy and Safety of Bevacizumab in Recurrent Sex Cord-Stromal Ovarian Tumors: Results of a Phase II Trial of the Gynecologic Oncology Group

    Science.gov (United States)

    Brown, Jubilee; Brady, William E.; Schink, Julian; Van Le, Linda; Leitao, Mario; Yamada, S. Diane; de Geest, Koen; Gershenson, David M.

    2014-01-01

    BACKGROUND The Gynecologic Oncology Group conducted this phase II trial to estimate the anti-tumor activity of bevacizumab and to determine the nature and degree of toxicity in patients with recurrent sex cord-stromal tumors of the ovary. METHODS A prospective, multi-institutional cooperative group trial was performed in women with recurrent measurable ovarian stromal tumor. Patients were allowed to have unlimited prior therapy, excluding bevacizumab. Bevacizumab 15 mg/kg was administered intravenously on day one of every 21 day cycle until disease progression or adverse effects prohibited further treatment. The primary endpoint was response rate (RR). Inhibin A and B levels were measured prior to each cycle, and the values were examined in relation to response and progression. RESULTS Thirty-six patients were enrolled, all of whom were eligible and evaluable. Patients received a median of nine cycles of treatment (range, 2-37 cycles). Six patients (16.7%) had partial responses (90% CI: 7.5%, 30.3%), 28 patients (77.8%) had stable disease, and two patients (5.6%) had increasing disease. This met the criterion for declaring the regimen active. The median PFS was 9.3 months. The median OS has not been reached. Two grade 4 toxicities occurred: hypertension and proteinuria; the most common grade 3 toxicities were hypertension (n=5) and pain (n=5). Inhibin A and B values were lower in patients who responded to treatment. CONCLUSIONS Bevacizumab has activity in the treatment of recurrent sex cord-stromal tumors of the ovary; toxicity is acceptable. Further investigation is warranted. PMID:24166194

  10. Heparin modulates chemokines in human endometrial stromal cells by interaction with tumor necrosis factor α and thrombin.

    Science.gov (United States)

    Spratte, Julia; Schönborn, Magdalena; Treder, Nora; Bornkessel, Frauke; Zygmunt, Marek; Fluhr, Herbert

    2015-05-01

    To study the impact of heparins on chemokines in decidualized human endometrial stromal cells (ESCs) in vitro. In vitro experiment. Research laboratory. Premenopausal women undergoing hysterectomy for benign reasons. ESCs were isolated from hysterectomy specimens, decidualized in vitro and incubated with unfractionated heparin and low-molecular-weight heparins (LMWHs) as well as tumor necrosis factor (TNF) α or thrombin with or without heparins. Chemokines CXCL1, CXCL5, CXCL8, CCL2, and CCL5 were measured with the use of ELISA, and CXCL5, CXCL8, CCL2, and CCL5 were detected with the use of real-time reverse-transcription polymerase chain reaction. Cell viability was determined with the use of a fluorometric assay. TNF-α and thrombin stimulated distinct patterns of chemokines in ESCs. Unfractionated heparin and LMWHs attenuated the TNF-α-mediated induction of CXCL8 and enhanced CXCL5, CCL2, and CCL5. The stimulating effect of thrombin on CXCL8 could be inhibited by heparin, whereas heparin had no impact on thrombin-induced CXCL1 and CCL2. Nuclear factor of transcription κB signaling mediated the effects of TNF-α. The effects of thrombin were mediated via extracellular signal-regulated protein kinases 1/2. Heparins have modulating effects on TNF-α- and thrombin-induced endometrial chemokines, which might have implications in the regulation of endometrial receptivity and early implantation. Copyright © 2015 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

  11. Stromal cells induce Th17 during Helicobacter pylori infection and in the gastric tumor microenvironment.

    Directory of Open Access Journals (Sweden)

    Irina V Pinchuk

    Full Text Available Gastric cancer is associated with chronic inflammation and Helicobacter pylori infection. Th17 cells are CD4(+ T cells associated with infections and inflammation; but their role and mechanism of induction during carcinogenesis is not understood. Gastric myofibroblasts/fibroblasts (GMF are abundant class II MHC expressing cells that act as novel antigen presenting cells. Here we have demonstrated the accumulation of Th17 in H. pylori-infected human tissues and in the gastric tumor microenvironment. GMF isolated from human gastric cancer and H. pylori infected tissues co-cultured with CD4(+ T cells induced substantially higher levels of Th17 than GMF from normal tissues in an IL-6, TGF-β, and IL-21 dependent manner. Th17 required interaction with class II MHC on GMF for activation and proliferation. These studies suggest that Th17 are induced during both H. pylori infection and gastric cancer in the inflammatory milieu of gastric stroma and may be an important link between inflammation and carcinogenesis.

  12. Evaluation of the Novel Monoclonal Antibody Against DOG1 as a Diagnostic Marker for Gastrointestinal Stromal Tumors

    International Nuclear Information System (INIS)

    Abdel-Hadi, M.; Hamam, S.M.; Bessa, S.S.

    2009-01-01

    Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. With the growing effectiveness and availability of first and second-generation tyrosine kinase inhibitor (TKI) drugs, the accurate diagnosis of GIST has become imperative. The problem is that some GISTs with KIT or Alpha-type platelet-derived growth factor receptor (PDGFRA) mutations may have low KIT expression by immunohistochemistry yet will still benefit from TKI drugs. Molecular analysis is a costly and laborious process. Therefore the emergence of a new sensitive immunohistochemical marker for GISTs would be ideal. Recently antibodies against D iscovered on GIST-1 ( DOG1) have been generated. The aim of this study was to evaluate the monoclonal DOG1.1 antibody as a diagnostic marker for GISTs and to compare immunohistochemical staining and diagnostic efficacy of DOG1.1 with that of KIT in GISTs. Materials and Methods: Forty seven paraffin embedded GISTs were immuno stained with both Kit and DOG1.1 antibodies. Immunoreactivity was graded semiquantitatively from 0 to 4. Some other mesenchymal tumors were included in the study and stained for both markers to test for their specificity. Results: Out of the 47 GISTs, 44 were immunoreactive for both KIT and DOG1.1 antibodies (93.62%). Two cases (4.25%) were KIT-positive DOG-negative and the remaining case was DOG-positive KIT-negative (2.13%). A statistically significant concordance was found between KIT and DOG1.1 immunoreactivity (p=0.004), with moderate agreement between immunostaining scores (kappa =0.379). As regards tumor site, a statistically significant association was found between high DOG1.1 scores and gastric GIST (p=0.008). High KIT and DOG1.1 immunostaining scores were significantly associated with high risk tumors (p=0.002 and p=0.002 respectively). DOG1.1 immunoreactivity was focal in more than half of the cases. The overall diagnostic accuracy of DOG1.1 was 96.5%, with a specificity and

  13. The current landscape of the mesenchymal stromal cell secretome: A new paradigm for cell-free regeneration.

    Science.gov (United States)

    Konala, Vijay Bhaskar Reddy; Mamidi, Murali Krishna; Bhonde, Ramesh; Das, Anjan Kumar; Pochampally, Radhika; Pal, Rajarshi

    2016-01-01

    The unique properties of mesenchymal stromal/stem cells (MSCs) to self-renew and their multipotentiality have rendered them attractive to researchers and clinicians. In addition to the differentiation potential, the broad repertoire of secreted trophic factors (cytokines) exhibiting diverse functions such as immunomodulation, anti-inflammatory activity, angiogenesis and anti-apoptotic, commonly referred to as the MSC secretome, has gained immense attention in the past few years. There is enough evidence to show that the one important pathway by which MSCs participate in tissue repair and regeneration is through its secretome. Concurrently, a large body of MSC research has focused on characterization of the MSC secretome; this includes both soluble factors and factors released in extracellular vesicles, for example, exosomes and microvesicles. This review provides an overview of our current understanding of the MSC secretome with respect to their potential clinical applications. Copyright © 2015 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

  14. Current View on Osteogenic Differentiation Potential of Mesenchymal Stromal Cells Derived from Placental Tissues.

    Science.gov (United States)

    Kmiecik, Gabriela; Spoldi, Valentina; Silini, Antonietta; Parolini, Ornella

    2015-08-01

    Mesenchymal stromal cells (MSC) isolated from human term placental tissues possess unique characteristics, including their peculiar immunomodulatory properties and their multilineage differentiation potential. The osteogenic differentiation capacity of placental MSC has been widely disputed, and continues to be an issue of debate. This review will briefly discuss the different MSC populations which can be obtained from different regions of human term placenta, along with their unique properties, focusing specifically on their osteogenic differentiation potential. We will present the strategies used to enhance osteogenic differentiation potential in vitro, such as through the selection of subpopulations more prone to differentiate, the modification of the components of osteo-inductive medium, and even mechanical stimulation. Accordingly, the applications of three-dimensional environments in vitro and in vivo, such as non-synthetic, polymer-based, and ceramic scaffolds, will also be discussed, along with results obtained from pre-clinical studies of placental MSC for the regeneration of bone defects and treatment of bone-related diseases.

  15. Podoplanin-positive Cancer-associated Stromal Fibroblasts in Primary Tumor and Synchronous Lymph Node Metastases of HER2-overexpressing Breast Carcinomas.

    Science.gov (United States)

    Niemiec, Joanna; Adamczyk, Agnieszka; Harazin-Lechowska, Agnieszka; Ambicka, Aleksandra; Grela-Wojewoda, Aleksandra; Majchrzyk, Kaja; Kruczak, Anna; Sas-Korczyńska, Beata; Ryś, Janusz

    2018-04-01

    We compared the status of stromal podoplanin-positive cancer-associated fibroblasts (ppCAFs) between primary tumors and paired synchronous lymph node metastases (LNMs) and analyzed the prognostic significance of tumoral ppCAFs in 203 patients with human epidermal growth factor receptor 2-positive breast carcinoma. ppCAFs were found in 167/203 and in 35/87 tumors and LNM, respectively. ppCAFs were most frequently found in tumors and corresponding LNM (n=52, 59.8%; p=0.001). However, for all LNMs (n=12) without ppCAFs, their paired tumors also lacked ppCAFs. In both tumors and LNMs, ppCAFs were α-smooth muscle actin-positive and cluster of differentiation 21 protein-negative, suggesting them not to be resident lymph node cells. Moreover, in our series, the presence of ppCAFs in tumors was borderline related to poor disease-free survival (p=0.058). These results speak in favor of a hypothesis suggesting ppCAFs accompany metastatic cancer cells migrating from tumor to LNMs. Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  16. Prediction of Tumor Recurrence in Patients with Non-Gastric Gastrointestinal Stromal Tumors Following Resection according to the Modified National Institutes of Health Criteria

    Science.gov (United States)

    Jang, Seung Hyeon; Kwon, Ji Eun; Kim, Jee Hyun; Lee, June Young; Kim, Sang Gyun; Kim, Joo Sung; Jung, Hyun Chae

    2014-01-01

    Background/Aims Few studies have investigated the prognosis of non-gastric gastrointestinal stromal tumors (GISTs) under the modified National Institutes of Health (NIH) consensus criteria in Korea. This study aims to clarify the clinical usefulness of the modified NIH criteria for risk stratification. Methods From January 2000 through October 2012, 88 patients who underwent curative resection for primary GISTs were included in this study. The enrolled patients were stratified to predict recurrence by the original NIH criteria and modified NIH criteria. Results In all, 88 patients had non-gastric GISTs, including 82 and 6 patients with GISTs of the small intestine and colorectum, respectively. The mean age was 57.3±13.0 years, and the median follow-up duration was 3.40 years (range, 0.02-12.76 years). All patients who were placed in the intermediate-risk category according to the original NIH criteria were reclassified into the high-risk category according to the modified NIH criteria. Therefore, the proportion of cases in the intermediate-risk category declined to 0.0% from 25.0% (22/88), and the proportion of cases in the high-risk category increased to 43.2% (38/88) from 18.2% (16/88) under the modified NIH criteria. Among the 22 reclassified patients, 6 (27.3%) suffered a recurrence during the observational period, and the recurrence rate of high-risk category patients was 36.8% (14/38). Conclusions Patients in the high-risk category according to the modified NIH criteria had a high GIST recurrence rate. Therefore, the modified NIH criteria are clinically useful in selecting patients who need imatinib adjuvant chemotherapy after curative surgical resection. PMID:25349597

  17. Intestinal stromal cells in mucosal immunity and homeostasis.

    Science.gov (United States)

    Owens, B M J; Simmons, A

    2013-03-01

    A growing body of evidence suggests that non-hematopoietic stromal cells of the intestine have multiple roles in immune responses and inflammation at this mucosal site. Despite this, many still consider gut stromal cells as passive structural entities, with past research focused heavily on their roles in fibrosis, tumor progression, and wound healing, rather than their contributions to immune function. In this review, we discuss our current knowledge of stromal cells in intestinal immunity, highlighting the many immunological axes in which stromal cells have a functional role. We also consider emerging data that broaden the potential scope of their contribution to immunity in the gut and argue that these so-called "non-immune" cells are reclassified in light of their diverse contributions to intestinal innate immunity and the maintenance of mucosal homeostasis.

  18. 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

    Energy Technology Data Exchange (ETDEWEB)

    Fuchigami, Takao [Department of Biochemistry and Genetics, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8544 (Japan); Department of Oral and Maxillofacial Surgery, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8544 (Japan); Kibe, Toshiro [Department of Oral and Maxillofacial Surgery, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8544 (Japan); Koyama, Hirofumi; Kishida, Shosei; Iijima, Mikio [Department of Biochemistry and Genetics, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8544 (Japan); Nishizawa, Yoshiaki [Kagoshima University Faculty of Medicine, 8-35-1 Sakuragaoka, Kagoshima 890-8544 (Japan); Hijioka, Hiroshi; Fujii, Tomomi [Department of Oral and Maxillofacial Surgery, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8544 (Japan); Ueda, Masahiro [Natural Science Centre for Research and Education, Kagoshima University, 1-21-24 Koorimoto, Kagoshima 890-8580 (Japan); Nakamura, Norifumi [Department of Oral and Maxillofacial Surgery, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8544 (Japan); Kiyono, Tohru [Department of Virology, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuouku, Tokyo 104-0045 (Japan); Kishida, Michiko, E-mail: kmichiko@m2.kufm.kagoshima-u.ac.jp [Department of Biochemistry and Genetics, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8544 (Japan)

    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

  19. Tumor Estromal Gastrintestinal de Localização Esofágica: Relato de Caso/ Gastrointestinal Stromal Tumor Location Esophageal: Case Report

    Directory of Open Access Journals (Sweden)

    Daniele Ribeiro Matsumoto

    2013-06-01

    Full Text Available Introdução: Os tumores estromais gastrintestinais (GIST são considerados as neoplasias mesenquimatosas mais comuns do trato gastrintestinal (TGI. São derivados das células intersticiais de Cajal, localizadas ao nível do plexo mioentérico e responsáveis pela motilidade gastrintestinal. Podem se originar em qualquer região do TGI, sendo apenas 5% provenientes do esôfago. Casuística: Foi relatado um caso de GIST de localização esofágica em um paciente que iniciou quadro de disfagia para alimentos sólidos e odinofagia, de caráter intermitente, acompanhado de náuseas e vômitos. Foram realizadas Seriografia contrastada de esôfago, Endoscopia Digestiva Alta, Tomografia Computadorizada de Abdome, o resultado histopatológico da biópsia da lesão foi inconclusivo e o diagnóstico foi confirmado pela imunohistoquímica que expressou CD117 (KIT pelas células neoplásicas. O serviço de oncologia de referência orientou a realização de cirurgia para ressecção tumoral, porém o paciente optou pela utilização do Mesilato de Imatinib (MI, tendo apresentado melhora progressiva do quadro clínico inicial. Discussão: O tratamento padrão para pacientes com GIST não metastático é a ressecção completa da lesão, pois oferece a maior chance de cura. Entretanto, o paciente optou somente pelo tratamento com o MI. Conclusão: Concluímos que o GIST deve ser considerado nas lesões exofíticas esofágicas e que o tratamento somente com o MI pode ser considerado, mesmo sabendo que o tratamento preconizado nestes casos é a ressecção cirúrgica, associada ao MI como terapia adjuvante, com melhora da sobrevida. Introduction: The gastrointestinal stromal tumor (GIST considered the most common mesenchymal neoplasm of the gastrointestinal tract (GIT. It is derived from interstitial cells of Cajal, located at the myenteric plexus and responsible for gastrointestinal motility. It can originate anywhere in the GI tract, and only 5% come from

  20. Experimental study of anti-tumor activity of direct current

    International Nuclear Information System (INIS)

    Ito, Hisao; Hashimoto, Shozo

    1989-01-01

    The anti-tumor activity of direct current combined with radiation was studied. The experiments were performed with fibrosarcomas (FSA, NFSA) syngenetic to C3H mice. Direct current (0.6mA, 120min) alone was effective to reduce the tumor sizes, but could not cure the tumors. When the direct current therapy (DC therapy) was combined with radiation the DC therapy following radiation was more effective than that before radiation. Using TCD 50 assay, the DC therapy enhanced the effect of a single dose of radiation with the dose-modifying factor of 1.2. However, tumor control rates by the combination therapy were more improved at the smaller doses of radiation than at the larger ones. When the single DC therapy (0.6mA, 120min) was applied immediately after the first radiation of fractionated one the combination therapy still showed the enhanced effect. However, both DC therapy and the radiation therapy were divided in three fractions, and the DC therapy (0.6mA, 40min) was applied after each radiation. Tumor growth retardation by the combination therapy was no different from that by radiation alone. This result suggests that there might be a minimum required dose of coulombs to show the effect of the combination therapy. (author)

  1. Intratumoral Delivery of Interferonγ-Secreting Mesenchymal Stromal Cells Repolarizes Tumor-Associated Macrophages and Suppresses Neuroblastoma Proliferation In Vivo.

    Science.gov (United States)

    Relation, Theresa; Yi, Tai; Guess, Adam J; La Perle, Krista; Otsuru, Satoru; Hasgur, Suheyla; Dominici, Massimo; Breuer, Christopher; Horwitz, Edwin M

    2018-02-12

    Neuroblastoma, the most common extracranial solid tumor in childhood, remains a therapeutic challenge. However, one promising patient treatment strategy is the delivery of anti-tumor therapeutic agents via mesenchymal stromal cell (MSC) therapy. MSCs have been safely used to treat genetic bone diseases such as osteogenesis imperfecta, cardiovascular diseases, autoimmune diseases, and cancer. The pro-inflammatory cytokine interferon-gamma (IFNγ) has been shown to decrease tumor proliferation by altering the tumor microenvironment (TME). Despite this, clinical trials of systemic IFNγ therapy have failed due to the high blood concentration required and associated systemic toxicities. Here, we developed an intra-adrenal model of neuroblastoma, characterized by liver and lung metastases. We then engineered MSCs to deliver IFNγ directly to the TME. In vitro, these MSCs polarized murine macrophages to the M1 phenotype. In vivo, we attained a therapeutically active TME concentration of IFNγ without increased systemic concentration or toxicity. The TME-specific IFNγ reduced tumor growth rate and increased survival in two models of T cell deficient athymic nude mice. Absence of this benefit in NOD SCID gamma (NSG) immunodeficient mouse model indicates a mechanism dependent on the innate immune system. IL-17 and IL-23p19, both uniquely M1 polarization markers, transiently increased in the tumor interstitial fluid. Finally, the MSC vehicle did not promote tumor growth. These findings reveal that MSCs can deliver effective cytokine therapy directly to the tumor while avoiding systemic toxicity. This method transiently induces inflammatory M1 macrophage polarization, which reduces tumor burden in our novel neuroblastoma murine model. Stem Cells 2018. © AlphaMed Press 2018.

  2. 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.

    Science.gov (United States)

    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

    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 interactively via these cytokines to create a microenvironment that leads to the extension of ameloblastomas. Copyright © 2014 Elsevier Inc. All rights reserved.

  3. Gastrointestinal Stromal Tumor of the Stomach with Narrow Stalk-Like Based, Uneven Protruding Appearance Presenting with Severe Acute Anemia despite Small Size

    Directory of Open Access Journals (Sweden)

    Tomomitsu Tahara

    2010-03-01

    Full Text Available We report the case of a 56-year-old woman who had a gastrointestinal stromal tumor (GIST of the stomach. She was admitted to our hospital for epigastric pain, nausea, and severe acute anemia (hemoglobin level 4.3 g/dl. Esophagogastroduodenoscopy revealed a narrow stalk-like based, hemorrhagic and uneven protruding lesion in the lesser curvature of the gastric upper corpus. Although the tumor was less than 2 cm in diameter and was probably a benign GIST according to histology, laparoscopy-assisted local resection was needed because the patient had continuous severe anemia and epigastric pain. Histological assessment showed that the elongated spindle-like tumor cells originated from the intrinsic muscle layer, and was shown with growth to the mucosal side, cropping out to the surface in most areas of the protruding lesion. Only a small part of the tumor was within nontumoral gastric mucosa. Most of the tumor cells demonstrated immunoreactivity for KIT and CD34 in the cytoplasm but not for αSMA, S100, and desmin. Mitotic activity (0/50 high power field and the labeling index for MIB-1 (about 1% were low. The GIST of the stomach described in this report was a rare case with a narrow stalk-like based, uneven protruding mass presenting with severe acute anemia despite small size.

  4. Current Perspectives on Desmoid Tumors: The Mayo Clinic Approach

    Energy Technology Data Exchange (ETDEWEB)

    Joglekar, Siddharth B. [Musculoskeletal Oncology, Mayo Clinic, Rochester, MN55905 (United States); Rose, Peter S.; Sim, Franklin, E-mail: sim.franklin@mayo.edu [Department of Orthopedics, Mayo Clinic, 200 1st ST SW, Rochester, MN 55905 (United States); Okuno, Scott [Department of Oncology, Mayo Clinic, Rochester, MN55905 (United States); Petersen, Ivy [Department of Radiation Oncology, Mayo Clinic, Rochester, MN55905 (United States)

    2011-08-08

    Desmoid tumors are a rare group of locally aggressive, non malignant tumors of fibroblastic origin that can lead to significant morbidity due to local invasion. Despite advances in the understanding of these tumors, their natural history is incompletely understood and the optimal treatment is still a matter of debate. Local control is the main goal of treatment and there has been a change in philosophy regarding the management of these tumors from aggressive surgical resection to function preservation. A multidisciplinary approach is essential to plan local control with acceptable morbidity. The current Mayo Clinic algorithm for the treatment of these tumors is based on institutional experience and the available evidence in the literature: asymptomatic/non progressive lesions away from vital structures are managed with observation and regular imaging; primary or recurrent desmoid tumors which are symptomatic or progressive or near vital structures are managed with wide surgical resection when wide surgical margins are possible with minimal functional and cosmetic loss. When positive or close surgical margins are likely, surgical resection with adjuvant radiotherapy or definitive radiotherapy is preferred. If likely functional or cosmetic deficit is unacceptable, radiotherapy is the treatment of choice. Unresectable lesions are considered for radiotherapy, chemotherapy or newer modalities however an unresectable lesion associated with a painful, functionless, infected extremity is managed with an amputation.

  5. Succinate Dehydrogenase Subunit B (SDHB Is Expressed in Neurofibromatosis 1-Associated Gastrointestinal Stromal Tumors (Gists: Implications for the SDHB Expression Based Classification of Gists

    Directory of Open Access Journals (Sweden)

    Jeanny H. Wang, Jerzy Lasota, Markku Miettinen

    2011-01-01

    Full Text Available Gastrointestinal Stromal Tumor (GIST is the most common mesenchymal tumor of the digestive tract. GISTs develop with relatively high incidence in patients with Neurofibromatosis-1 syndrome (NF1. Mutational activation of KIT or PDGFRA is believed to be a driving force in the pathogenesis of familial and sporadic GISTs. Unlike those tumors, NF1-associated GISTs do not have KIT or PGDFRA mutations. Similarly, no mutational activation of KIT or PDGFRA has been identified in pediatric GISTs and in GISTs associated with Carney Triad and Carney-Stratakis Syndrome. KIT and PDGFRA-wild type tumors are expected to have lesser response to imatinib treatment. Recently, Carney Triad and Carney-Stratakis Syndrome -associated GISTs and pediatric GISTs have been shown to have a loss of expression of succinate dehydrogenase subunit B (SDHB, a Krebs cycle/electron transport chain interface protein. It was proposed that GISTs can be divided into SDHB- positive (type 1, and SDHB-negative (type 2 tumors because of similarities in clinical features and response to imatinib treatment. In this study, SDHB expression was examined immunohistochemically in 22 well-characterized NF1-associated GISTs. All analyzed tumors expressed SDHB. Based on SDHB-expression status, NF1-associated GISTs belong to type 1 category; however, similarly to SDHB type 2 tumors, they do not respond well to imatinib treatment. Therefore, a simple categorization of GISTs into SDHB-positive and-negative seems to be incomplete. A classification based on both SDHB expression status and KIT and PDGFRA mutation status characterize GISTs more accurately and allow subdivision of SDHB-positive tumors into different clinico-genetic categories.

  6. Results on prognostic value of mutations in localized gastrointestinal stromal tumors (GIST: in one single center Valor pronóstico de las mutaciones en tumores estromales gastrointestinales localizados (GIST: resultados de un solo centro

    Directory of Open Access Journals (Sweden)

    Marina Garcés-Albir

    2012-08-01

    Full Text Available Introduction: to study the prognostic value of mutations in KIT or PDGFRA in gastrointestinal stromal tumors (GIST managed in our department. Materials and methods: forty five patients with localized GIST underwent surgery between 1998 and 2010. Thirty six patients were enrolled in a retrospective study. DNA was isolated from 3 to 5 µm sections of fixed and paraffin-embedded tissue. Exon 9, 11, 13 and 17 of c-kit gene and exon 12 and 18 of PDGFRA were amplified by PCR and sequenced. Results: tumors with mutations were larger at the surgery and showed higher mitotic count (p 50 mitosis/HPF (42 vs. 88%, p < 0.03. Multivariate analyses indicated that the mutations, mitotic counts, and tumor size were independent prognostic factors for survival in patients with localized GIST. Conclusions: in this series, having a detected mutation is a poor prognostic factor with significantly increased recurrence rate and shortens survival.

  7. Mutations in exons 9 and 13 of KIT gene are rare events in gastrointestinal stromal tumors. A study of 200 cases.

    Science.gov (United States)

    Lasota, J; Wozniak, A; Sarlomo-Rikala, M; Rys, J; Kordek, R; Nassar, A; Sobin, L H; Miettinen, M

    2000-10-01

    Gastrointestinal stromal tumors (GISTs), the most common mesenchymal tumors of the gastrointestinal tract, typically express the KIT protein. Activating mutations in the juxtamembrane domain (exon 11) of the c-kit gene have been shown in a subset of GISTs. These mutations lead into ligand-independent activation of the tyrosine kinase of c-kit, and have a transforming effect in vitro. Several groups have studied the clinical implication of the c-kit mutation status of exon 11 in GISTs and a possible relationship between c-kit mutations and malignant behavior has been established. Recently, a 1530ins6 mutation in exon 9 and missense mutations, 1945A>G in exon 13 of the c-kit gene were reported. The frequency and clinical importance of these findings are unknown. In this study we evaluated 200 GISTs for the presence of mutations in exons 9 and 13 of c-kit. Six cases revealed 1530ins6 mutation in exon 9 and two cases 1945A>G mutation in exon 13. All tumors with mutations in exon 9 and 13 lacked mutations in exon 11 of c-kit. None of the analyzed tumors had more than one type of c-kit mutation. All but one of the eight tumors with mutations in exon 9 or 13 of the c-kit gene were histologically and clinically malignant. All four of six cases with exon 9 mutation of which location of primary tumor was known, were small intestinal, suggesting that this type of mutation could preferentially occur in small intestinal tumors. Exon 9 and 13 mutations seem to be rare, and they cover only a small portion (8%) of the balance of GISTs that do not have mutations in exon 11 of c-kit. This finding indicates that other genetic alterations may activate c-kit in GISTs, or that KIT is not activated by mutations in all cases.

  8. Remarkable effects of imatinib in a family with young onset gastrointestinal stromal tumors and cutaneous hyperpigmentation associated with a germline KIT-Trp557Arg mutation: case report and literature overview

    NARCIS (Netherlands)

    Farag, S.; van der Kolk, L. E.; van Boven, H. H.; van Akkooi, A. C. J.; Beets, G. L.; Wilmink, J. W.; Steeghs, N.

    2017-01-01

    Gastrointestinal stromal tumors (GISTs) occur mostly sporadically. GISTs associated with a familial syndrome are very rare and are mostly wild type for KIT and platelet-derived growth factor alpha (PDGFRA). To date 35 kindreds and 8 individuals have been described with GISTs associated with germline

  9. Sertoli-Leydig cell tumor

    Science.gov (United States)

    Sertoli-stromal cell tumor; Arrhenoblastoma; Androblastoma; Ovarian cancer - Sertoli-Leydig cell tumor ... PA: Elsevier Saunders; 2013:chap 13. Prat J. Ovarian sex cord - stromal and steroid cell tumors. In: Mutter GL, Prat J, eds. Pathology of ...

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

    Science.gov (United States)

    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. © The Author(s) 2015.

  11. Familial Progressive Hyperpigmentation, Cutaneous Mastocytosis, and Gastrointestinal Stromal Tumor as Clinical Manifestations of Mutations in the c-KIT Receptor Gene.

    Science.gov (United States)

    Piqueres-Zubiaurre, Tatiana; Martínez de Lagrán, Zuriñe; González-Pérez, Ricardo; Urtaran-Ibarzabal, Amaia; Perez de Nanclares, Guiomar

    2017-01-01

    Familial progressive hyperpigmentation (FPH) is an autosomal dominant disorder characterized by the appearance of hyperpigmented patches on the skin from early infancy that increase in size and number with age. We report the clinical and molecular studies of an 11-year-old boy who had areas of hyperpigmentation since birth that had spread across his body as irregular hyperpigmented macules and papules, and include relevant history in family members. Affected members of his family shared a mutation in the c-KIT gene. All had progressive hyperpigmentation, in some cases accompanied by gastrointestinal stromal tumors and mastocytoma. There have been few reports of familial progressive hyperpigmentation together with systemic manifestations. Molecular analysis of c-KIT should be considered in the presence of FPH with systemic involvement. © 2016 Wiley Periodicals, Inc.

  12. PHYLLOID TUMORS OF MAMMARY GLANDS. CURRENT STATE OF THE PROBLEM

    Directory of Open Access Journals (Sweden)

    A. D. Zikiryakhodzhaev

    2017-01-01

    Full Text Available Phylloid (leaf-shaped breast tumors are a rare disease and constitute 0.3–0.5% of all breast tumors. Due to the rare frequency of occurrence, as well as the small number of randomized studies that have been conducted on this pathology, there is currently no standardized approach to the diagnosis and treatment of phylloid tumors. The reports about these rare cases appearing in the literature are, as a rule, descriptive, which only emphasizes the difficulty of differential diagnosis, the development of the correct tactics for treating such patients. In connection with the rarity, it is very difficult to diagnose correctly this pathology, which requires a highly qualified doctor as a diagnostician in the initial contact with such a patient, and a pathologist doctor who establishes the final morphological diagnosis. Often, leaf-shaped tumors are mistaken for mammary fibroadenomas. Such difficulties in correct diagnosis in the preoperative period can lead to errors in the planning of treatment. Also, the recommendations for the treatment of patients with this diagnosis are not fully understood, since up to now there are no accepted treatment standards in both Russian and foreign recommendations. Due to the fact that this pathology of mammary glands is rare, the principles of treatment are based on small retrospective studies and clinical observations. In this review, we will discuss the results of major retrospective studies, including data on epidemiology, etiology, diagnostic approach, strategies and results of treatment of this complex group of breast pathologies.

  13. Inhibition of platelet-derived growth factor receptor α by MEDI-575 reduces tumor growth and stromal fibroblast content in a model of non-small cell lung cancer.

    Science.gov (United States)

    Laing, Naomi; McDermott, Brenda; Wen, Shenghua; Yang, David; Lawson, Deborah; Collins, Mike; Reimer, Corinne; Hall, Peter A; Andersén, Harriet; Snaith, Michael; Wang, Xin; Bedian, Vahe; Cao, Zhu A; Blakey, David

    2013-06-01

    Platelet-derived growth factor receptor α (PDGFRα) is a receptor tyrosine kinase that promotes cell survival and is expressed in both the tumor and the stromal components of human cancers. We have developed a fully human monoclonal antibody, MEDI-575, that selectively binds to human PDGFRα with high affinity, with no observable affinity for murine PDGFRα. To more fully characterize the role of PDGFRα in the regulation of tumor stroma, we evaluated the in vivo antitumor effects of MEDI-575 in tumor-bearing severe combined immunodeficient (SCID) mice and in genetically altered SCID mice expressing human PDGFRα in place of murine PDGFRα. We used the Calu-6 non-small cell lung cancer model because it lacks an in vitro proliferative response to PDGFRα activation. Antitumor activity was observed when the study was performed in mice expressing the human receptor, but no activity was observed in the mice expressing the murine receptor. Immunohistologic analysis of the tumors from mice expressing human PDGFRα showed a highly significant reduction in stromal fibroblast content and only minor changes in tumor proliferative index in tumors exposed to MEDI-575 compared with the results seen in vehicle-treated tumors or in tumors from mice expressing murine PDGFRα. Additional in vitro studies indicated that exposure of primary cancer-associated fibroblasts to MEDI-575 can directly affect proliferation and key signaling pathways in these cells. These results highlight the potential for observing antitumor activity with MEDI-575 through modulation of the stromal component of tumors and confirm that the PDGFRα pathway can play a role in maintaining a tumor microenvironment conducive to tumor growth.

  14. Lack of any relationship between ABO and Rh blood groups and clinicopathological features in patients with gastrointestinal stromal tumors: Turkish Oncology Group.

    Science.gov (United States)

    Ürün, Yüksel; Utkan, Güngör; Yalcin, Şuayib; Coşkun, Hasan Şenol; Koçer, Murat; Özdemir, Nuriye Yildirim; Kaplan, Mehmet Ali; Arslan, Ülkü Yalçintaş; Özdemir, Feyyaz; Öztuna, Derya; Akbulut, Hakan; İçli, Fikri

    2012-01-01

    An association between the ABO blood group and the risk of certain malignancies, including pancreatic and gastric cancer, has been reported previously. However, it is unclear whether this association is valid for gastrointestinal stromal tumors (GIST). In this study, ABO blood groups and the Rh factor were investigated in a series of GIST cases. In 162 patients with GIST, blood group and Rh factor were examined and compared with a control group of 3,022,883 healthy volunteer blood donors of the Turkish Red Crescent between 2004 and 2011. The relationship of blood groups with tumor size, mitotic activity, and age were also evaluated. Overall, the ABO blood group and Rh factor distributions of the 162 patients with GIST were similar to those of the general population. There were no significant differences between both ABO blood types and Rh factor in terms of tumor size, mitotic activity, and age. This is the first study reported on this issue. In our study, we didn't find any relationship between GIST and ABO blood group and Rh factor. However further studies with larger number of patients are needed to establish the role of blood groups in this population.

  15. Rapid On-Site Evaluation by Endosonographers during Endoscopic Ultrasonography-Guided Fine-Needle Aspiration for Diagnosis of Gastrointestinal Stromal Tumors

    Science.gov (United States)

    Tamura, Takashi; Yamashita, Yasunobu; Ueda, Kazuki; Kawaji, Yuki; Itonaga, Masahiro; Murata, Shin-ichi; Yamamoto, Kaori; Yoshida, Takeichi; Maeda, Hiroki; Maekita, Takao; Iguchi, Mikitaka; Tamai, Hideyuki; Ichinose, Masao; Kato, Jun

    2017-01-01

    Background/Aims Endoscopic ultrasonography-guided fine-needle aspiration (EUS-FNA) has been used to diagnose gastrointestinal submucosal tumors (SMTs). Although rapid on-site evaluation (ROSE) has been reported to improve the diagnostic accuracy of EUS-FNA for pancreatic lesions, on-site cytopathologists are not routinely available. Given this background, the usefulness of ROSE by endosonographers themselves for pancreatic tumors has also been reported. However, ROSE by endosonographers for diagnosis of SMT has not been reported. The aim of this study was to evaluate the diagnostic accuracy of EUS-FNA with ROSE by endosonographers for SMT, focusing on diagnosis of gastrointestinal stromal tumor (GIST), compared with that of EUS-FNA alone. Methods Twenty-two consecutive patients who underwent EUS-FNA with ROSE by endosonographers for SMT followed by surgical resection were identified. Ten historical control subjects who underwent EUS-FNA without ROSE were used for comparison. Results The overall diagnostic accuracy for SMT was significantly higher in cases with than without ROSE (100% vs. 80%, p=0.03). The number of needle passes by FNA with ROSE by endosonographers tended to be fewer, although accuracy was increased (3.3±1.3 vs. 5.9±3.8, p=0.06). Conclusions ROSE by endosonographers during EUS-FNA for SMT is useful for definitive diagnosis, particularly for GIST. PMID:28103654

  16. [A case of rectal gastrointestinal stromal tumor in an elderly patient who was successfully treated with imatinib mesylate with no significant adverse events].

    Science.gov (United States)

    Gomi, Kuniyuki; Mihara, Motohiro; Abe, Mitsutoshi; Ikeda, Yoshiaki; Shimada, Kou; Maruyama, Kiyotomi; Kajikawa, Shoji; Shirota, Hiroshi

    2014-01-01

    An 89-year-old male patient was found to have a mass with a diameter of 54 mm in the pelvic cavity, connected to the rectum, and was diagnosed with a gastrointestinal stromal tumor (GIST)of the rectum by transrectal biopsy. The patient was treated continuously with 400mg/day of imatinib mesylate with no significant adverse events, and the tumor gradually reduced in size. The tumor reduced in size to a diameter of 24 mm at 57 months post-treatment, and a partial response has been maintained for 60 months. Colorectal GIST is rare, comprising 5% of all GIST cases, and surgical resection is the first choice of treatment. In this case, due to a lack of consent, we chose imatinib mesylate as the treatment. However, imatinib mesylate has been reported to induce adverse events more frequently in older patients, and thus we took care to reduce the treatment dosage. We report this case to highlight that a normal quantity of imatinib mesylate can be administered, with no significant adverse events.

  17. Prognostic Factors of Patients with Gastric Gastrointestinal Stromal Tumor after Curative Resection: A Retrospective Analysis of 406 Consecutive Cases in a Multicenter Study.

    Science.gov (United States)

    Kim, In-Hwan; Kwak, Sang-Gyu; Chae, Hyun-Dong

    2015-01-01

    Gastric gastrointestinal stromal tumors (GISTs) have a highly variable clinical course, and recurrent disease sometimes develops despite curative surgery. This study was undertaken to investigate the surgical role in treating gastric GISTs and evaluate the clinicopathological features of a large series of patients who underwent curative resection for gastric GISTs to clarify which features were independent prognostic factors. The clinicopathological data of 406 patients with gastric GISTs who underwent curative resection at 4 university hospitals in Daegu, South Korea, from March 1998 to March 2012 were reviewed. All cases were confirmed as gastric GISTs by immunohistochemical staining, in which CD117 or CD34 was positive. Clinical follow-up was performed periodically, and disease-free survival rates were retrospectively investigated using the medical records. The mean follow-up period was 42.9 months (range: 2-166). There were 11 recurrent patients (2.7%). Due to the small number of recurrences, age, sex and location were controlled using propensity score matching before performing any statistical analysis. Tumor size, mitotic count, NIH classification, and cellularity were judged to be independent prognostic factors for recurrence by univariate analysis. In a multivariate analysis, tumor size and mitotic count were significantly and independently related to recurrence, and tumor size was determined to be the most important prognostic factor for recurrence after curative resection (hazard ratio: 1.204; p < 0.01). The results of this multicenter study demonstrate that disease-free survival rates are good. Tumor size was disclosed as the most important factor for recurrence in gastric GIST patients who underwent radical resection. 2015 S. Karger AG, Basel.

  18. Comparison of stromal CD10 expression in benign, borderline, and malignant phyllodes tumors among Egyptian female patients

    Directory of Open Access Journals (Sweden)

    Wael S Ibrahim

    2011-01-01

    Full Text Available Background: Phyllodes tumors are group of biphasic fibroepithelial tumors of the breast of varying malignant potential, ranging from benign tumors to fully malignant sarcomas. According to the Egyptian National Cancer Institute, female malignant cases showed appreciable increase in the recent time period for breast cancer with the malignant phyllodes tumors representing 0.41% of cases in the year 2003-2004. Aims: This is an immunohistochemical study to compare CD10 expression in benign, borderline, and malignant phyllodes tumors, in order to highlight its diagnostic and prognostic values. Materials and Methods: This study conducted 34 Egyptian female cases of phyllodes tumors of different grades to be studied histologically and immunohistochemically using antibodies against CD10. Statistical Analysis: The Chi-square test was used to determine differences in CD10 expression between benign, borderline, and malignant tumors. One-way ANOVA test was used to determine whether the difference was significant. Significance was established at P<0.05. Results: In the 24 cases of benign phyllodes tumors, only four cases (16.7% showed positive CD10 reactivity. Three cases (60% out of five borderline phyllodes tumors showed positive CD10 reactivity, while four (80% out of five cases of malignant phyllodes tumors showed positive CD10 staining. Conclusion: From these highly significant results, we believe that there is a strong correlation between CD10 expression and tumor grade, which could be an important observation that may have both diagnostic and prognostic implications as well as promising potential target for development of novel therapies.

  19. Loss of the Y-chromosome in the primary metastasis of a male sex cord stromal tumor : Pathogenetic implications

    NARCIS (Netherlands)

    de Graaff, WE; van Echten, J; van der Veen, AY; Sleijfer, DT; Timmer, A; de Jong, B; Schraffordt Koops, H.

    1999-01-01

    The first published chromosomal pattern of the retroperitoneal lymph node metastasis of a malignant gonadal stroma cell tumor of the adult testis is presented. Karyotyping showed structural chromosomal abnormalities and loss of the Y-chromosome. This loss was confirmed in primary tumor and

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

    Directory of Open Access Journals (Sweden)

    Ming-Ze Ma

    2014-03-01

    Full Text Available 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.

  1. Current Concepts and Occurrence of Epithelial Odontogenic Tumors: I. Ameloblastoma and Adenomatoid Odontogenic Tumor

    Science.gov (United States)

    Kim, Yeon Sook

    2013-01-01

    Ameloblastomas and adenomatoid odontogenic tumors (AOTs) are common epithelial tumors of odontogenic origin. Ameloblastomas are clinico-pathologically classified into solid/multicystic, unicystic, desmoplastic, and peripheral types, and also divided into follicular, plexiform, acanthomatous, granular types, etc., based on their histological features. Craniopharyngiomas, derived from the remnants of Rathke's pouch or a misplaced enamel organ, are also comparable to the odontogenic tumors. The malignant transformation of ameloblastomas results in the formation of ameloblastic carcinomas and malignant ameloblastomas depending on cytological dysplasia and metastasis, respectively. AOTs are classified into follicular, extrafollicular, and peripheral types. Ameloblastomas are common, have an aggressive behavior and recurrent course, and are rarely metastatic, while AOTs are hamartomatous benign lesions derived from the complex system of the dental lamina or its remnants. With advances in the elucidation of molecular signaling mechanisms in cells, the cytodifferentiation of epithelial tumor cells in ameloblastomas and AOTs can be identified using different biomarkers. Therefore, it is suggested that comprehensive pathological observation including molecular genetic information can provide a more reliable differential diagnosis for the propagation and prognosis of ameloblastomas and AOTs. This study aimed to review the current concepts of ameloblastomas and AOTs and to discuss their clinico-pathological features relevant to tumorigenesis and prognosis. PMID:23837011

  2. Gastrointestinal stromal tumor of the vermiform appendix mimicking Meckel’s diverticulum: Case report with literature review

    Directory of Open Access Journals (Sweden)

    Jae Min Chun

    2016-01-01

    Conclusion: Primary appendiceal GIST occur at a very low rate and their symptoms are nonspecific. Accordingly, rare tumors of appendix including GISTs should be considered in the differential diagnosis of atypical symptoms or image findings.

  3. Cost-effectiveness of sunitinib as second-line treatment for gastrointestinal stromal tumor in the People’s Republic of China

    Directory of Open Access Journals (Sweden)

    Li J

    2017-01-01

    Full Text Available Jian Li,1 Hong Ye Ren,2 Juanjuan Zhang,2 Peng Dong,2 Yan Wang,3 Andrea L Stevens,3 Yi Han,3 Min Huang4 1Laboratory of Carcinogenesis and Translational Research for the Ministry of National Education, Department of GI Oncology, Peking University School of Oncology, Beijing Cancer Hospital & Institute, 2Pfizer Inc., Beijing, People’s Republic of China; 3WG Consulting, New York, NY, USA; 4School of Pharmacy, Sun Yat-sen University, Guangzhou, Guangdong, People’s Republic of China Objective: To evaluate the cost-effectiveness of sunitinib as a second-line treatment in patients with advanced gastrointestinal stromal tumors that no longer respond to imatinib 400 mg/d, compared with imatinib 600 mg/d, 800 mg/d, or best supportive care (BSC in the People’s Republic of China. Methods: This study was conducted from the government payer’s perspective with a time horizon of 5 years. Three health states were considered: progression-free survival, disease progression survival, and death, with a cycle length of 6 weeks. Probabilities of disease progression and death were estimated based on survival functions using exponential distribution and progression survival data in the clinical trials. Drug costs were based on drug retail prices and the patient assistance program in the People’s Republic of China, and adverse event management costs were based on published data and/or expert opinion. Uncertainties for parameters in the study were addressed through one-way deterministic and probabilistic sensitivity analysis. Results: When sunitinib was compared with imatinib 600 mg/d and BSC, the incremental cost-effectiveness ratio was RMB75,715 with RMB121,080 per quality-adjusted life-year (QALY gained. Sunitinib demonstrated lower costs and higher QALYs than imatinib 800 mg/d. In the probabilistic sensitivity analysis, the willingness-to-pay per QALY gained was set to be three times the per capita gross domestic product of the People’s Republic of

  4. Spontaneous Formation of Tumorigenic Hybrids between Breast Cancer and Multipotent Stromal Cells Is a Source of Tumor Heterogeneity

    OpenAIRE

    Rappa, Germana; Mercapide, Javier; Lorico, Aurelio

    2012-01-01

    Breast cancer progression involves cancer cell heterogeneity, with generation of invasive/metastatic breast cancer cells within populations of nonmetastatic cells of the primary tumor. Sequential genetic mutations, epithelial-to-mesenchymal transition, interaction with local stroma, and formation of hybrids between cancer cells and normal bone marrow–derived cells have been advocated as tumor progression mechanisms. We report herein the spontaneous in vitro formation of heterotypic hybrids be...

  5. A phase 1 study of the heat shock protein 90 inhibitor retaspimycin hydrochloride (IPI-504) in patients with gastrointestinal stromal tumors or soft tissue sarcomas

    Science.gov (United States)

    Wagner, Andrew J.; Chugh, Rashmi; Rosen, Lee S.; Morgan, Jeffrey A.; George, Suzanne; Gordon, Michael; Dunbar, Joi; Normant, Emmanuel; Grayzel, David; Demetri, George D.

    2015-01-01

    Purpose Heat shock protein 90 (Hsp90) is required for the proper folding, function, and stability of various client proteins, two of which (KIT and PDGFRα) are critical in the pathogenesis and progression of gastrointestinal stromal tumors (GIST). This phase 1 study investigated the safety and maximum tolerated dose (MTD) of retaspimycin hydrochloride (IPI-504), a novel potent and selective Hsp90 inhibitor, in patients with metastatic and/or unresectable GIST or other soft-tissue sarcomas (STS). Experimental Design IPI-504 was administered intravenously at doses ranging from 90 to 500 mg/m2 twice weekly for 2 weeks on/1 week off. Safety, pharmacokinetic, and pharmacodynamic profiles were determined. Response was assessed by Response Evaluation Criteria for Solid Tumors (RECIST) 1.0 and optionally via 18-fluorodeoxyglucose positron emission tomography (18-FDG-PET) imaging. Results Fifty-four patients received IPI-504; 37 with GIST and 17 with other STS. The MTD was 400 mg/m2 twice weekly for 2 weeks on/1 week off. Common related adverse events were fatigue (59%), headache (44%), and nausea (43%). Exposure to IPI-504, 17-AAG, and 17-AG increased with IPI-504 dose. Stable disease (SD) was observed in 70% (26/37) of patients with GIST and 59% (10/17) of patients with STS. There was one confirmed partial response (PR) in a patient with GIST and one PR in a patient with liposarcoma. Metabolic partial responses occurred in 11/29 (38%) of GIST patients. Conclusions In this study of advanced GIST or other STS, IPI-504 was generally well-tolerated with some evidence of anti-tumor activity, serving as a clinical proof-of-concept that HSP90 inhibition remains a promising strategy. PMID:24045182

  6. Initial application of transanal endoscopic microsurgery for high-risk lower rectal gastrointestinal stromal tumor after imatinib mesylate neoadjuvant chemotherapy: A case report.

    Science.gov (United States)

    Liu, Qiaofei; Zhong, Guangxi; Zhou, Weixun; Lin, Guole

    2017-07-01

    The lower rectal gastrointestinal stromal tumor (GIST) is a rare entity and warrants special attentions because of the considerations of preserving of anal and urinal functions. Neoadjuvant therapy with imatinib mesylate (IM) has achieved great success in GIST, which potentially extends the applications of function-preserving minimally invasive surgical procedures. Transanal endoscopic microsurgery (TEM) is a well-developed minimally invasive technique for benign tumors in lower rectum. Herein, we reported the initial application of TEM for high risk GIST after IM treatment. A 52-year-old woman suffered mild lower abdominal pain and perianal discomfort. Physical examination found a soft mass 4 cm far away from anal verge. Rectal MRI and transrectal ultrasound (TRUS) showed that there was a 1.9 × 1.6 cm submucosal mass in the lower rectum. The incisional biopsy was performed and the pathological result reported it was a high-risk GIST. High-risk lower rectal GIST. IM was given for neoadjuvant therapy. Then TEM was adopted to resect the residual tumor. IM was restored 4 weeks after surgery. The final pathological results reported the margin was clear. After an 18-month follow up, no recurrence and metastasis was found and the patient had a satisfactory anal and urinal functions. TEM in combination with IM could be a practical strategy for the high-risk lower rectal GIST simultaneously to achieve curative resection and to preserve the anal and urinal functions that can significantly improve the life quality of the patients.

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

    Directory of Open Access Journals (Sweden)

    Wu L

    2014-10-01

    Full Text Available Lile Wu, Zhongqiang Zhang, Hongliang Yao, Kuijie Liu, Yu Wen, Li Xiong Department of General Surgery, Second Xiangya Hospital of Central South University, Changsha, People's Republic of China 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

  8. Fibroadenoma and phyllodes tumors of anogenital mammary-like glands: a series of 13 neoplasms in 12 cases, including mammary-type juvenile fibroadenoma, fibroadenoma with lactation changes, and neurofibromatosis-associated pseudoangiomatous stromal hyperplasia with multinucleated giant cells.

    Science.gov (United States)

    Kazakov, Dmitry V; Spagnolo, Dominic V; Stewart, Colin J; Thompson, Jane; Agaimy, Abbas; Magro, Gaetano; Bisceglia, Michele; Vazmitel, Marina; Kacerovska, Denisa; Kutzner, Heinz; Mukensnabl, Petr; Michal, Michal

    2010-01-01

    The authors present a series of 13 fibroepithelial neoplasms involving anogenital mammary-like glands, all occurring in 12 female patients, whose age at diagnosis ranged from 30 to 51 years (mean, 38 y; median, 42 y). All women presented with a solitary asymptomatic nodule in the vulva (n=8), perineum (n=2), or near the anus (n=2) ranging in size from 1.5 to 4.5 cm. Microscopically, 8 lesions were classified as fibroadenoma, and 5, including 1 recurrent tumor, as phyllodes tumor, of which 1 was benign and 4 low-grade malignant. In addition to conventional findings, we describe several hitherto unreported features including juvenile fibroadenoma-like proliferation, fibroadenoma with lactation change, and pseudoangiomatous stromal hyperplasia with multinucleated stromal giant cells in a patient with neurofibromatosis, type 1 all constituting potential diagnostic pitfalls, which are best averted by using the same approach to diagnosis as for their analogous mammary counterparts.

  9. The Interaction Between Human Papillomaviruses and the Stromal Microenvironment.

    Science.gov (United States)

    Woodby, B; Scott, M; Bodily, J

    2016-01-01

    Human papillomaviruses (HPVs) are small, double-stranded DNA viruses that replicate in stratified squamous epithelia and cause a variety of malignancies. Current efforts in HPV biology are focused on understanding the virus-host interactions that enable HPV to persist for years or decades in the tissue. The importance of interactions between tumor cells and the stromal microenvironment has become increasingly apparent in recent years, but how stromal interactions impact the normal, benign life cycle of HPVs, or progression of lesions to cancer is less understood. Furthermore, how productively replicating HPV impacts cells in the stromal environment is also unclear. Here we bring together some of the relevant literature on keratinocyte-stromal interactions and their impacts on HPV biology, focusing on stromal fibroblasts, immune cells, and endothelial cells. We discuss how HPV oncogenes in infected cells manipulate other cells in their environment, and, conversely, how neighboring cells may impact the efficiency or course of HPV infection. © 2016 Elsevier Inc. All rights reserved.

  10. Fractal analysis of nuclear histology integrates tumor and stromal features into a single prognostic factor of the oral cancer microenvironment

    International Nuclear Information System (INIS)

    The lack of prognostic biomarkers in oral squamous cell carcinoma (OSCC) has hampered treatment decision making and survival in OSCC remains poor. Histopathological features are used for prognostication in OSCC and, although useful for predicting risk, manual assessment of histopathology is subjective and labour intensive. In this study, we propose a method that integrates multiple histopathological features of the tumor microenvironment into a single, digital pathology-based biomarker using nuclear fractal dimension (nFD) analysis. One hundred and seven consecutive OSCC patients diagnosed between 1998 and 2006 in Calgary, Canada were included in the study. nFD scores were generated from DAPI-stained images of tissue microarray (TMA) cores. Ki67 protein expression was measured in the tumor using fluorescence immunohistochemistry (IHC) and automated quantitative analysis (AQUA®). Lymphocytic infiltration (LI) was measured in the stroma from haematoxylin-eosin (H&E)-stained TMA slides by a pathologist. Twenty-five (23.4%) and 82 (76.6%) patients were classified as high and low nFD, respectively. nFD was significantly associated with pathological tumor-stage (pT-stage; P = 0.01) and radiation treatment (RT; P = 0.01). High nFD of the total tumor microenvironment (stroma plus tumor) was significantly associated with improved disease-specific survival (DSS; P = 0.002). No association with DSS was observed when nFD of either the tumor or the stroma was measured separately. pT-stage (P = 0.01), pathological node status (pN-status; P = 0.02) and RT (P = 0.03) were also significantly associated with DSS. In multivariate analysis, nFD remained significantly associated with DSS [HR 0.12 (95% CI 0.02-0.89, P = 0.04)] in a model adjusted for pT-stage, pN-status and RT. We also found that high nFD was significantly associated with high tumor proliferation (P < 0.0001) and high LI (P < 0.0001), factors that we and others have shown to be associated with improved survival in OSCC

  11. Stromal myofibroblasts in breast cancer: relations between their occurrence, tumor grade and expression of some tumour markers.

    Directory of Open Access Journals (Sweden)

    Maciej Zabel

    2006-06-01

    Full Text Available It is suggested that tumour stromal myofibroblasts exert an unfavourable effect on the biology of breast cancer. We are aware of only a single study which examined relationships between manifestation of myofibroblasts in the stroma of breast cancer and clinicopathological data of the patients. The present study was aimed at estimation of the effect exerted by myofibroblasts present in the tumour stroma on principal pathological parameters and on expression of Ki67, P53 and HER-2 proteins in the group of the most frequent breast cancers, the ductal cancers. In paraffin sections of 60 ductal breast cancers (20 cases in G1, 20 in G2 and 20 in G3, immunohistochemical reactions were performed to detect expression of smooth muscle actin (SMA in order to visualize myofibroblasts, Ki67, P53 and HER-2. The studies demonstrated that the most numerous myofibroblasts were present in G3 cases and they were the least frequent in G1 cases (P = 0.02. Positive correlations were observed between the presence of myofibroblasts in tumour stroma and expression of Ki67 and HER-2 in breast cancer cells in the entire group (P < 0.001 and P = 0.001, respectively, in G2 cases (P = 0.003 and P = 0.03 and in G3 cases (P = 0.01 and P = 0.03. Considering that the higher grade, Ki67 and HER-2 are thought to represent unfavourable prognostic factors, the elevated content of myofibroblasts in tumour stroma is probably typical for cases with worse prognosis.

  12. Childhood brain tumors: epidemiology, current management and future directions.

    Science.gov (United States)

    Pollack, Ian F; Jakacki, Regina I

    2011-07-26

    Brain tumors are the most common solid tumors in children. With the increasingly widespread availability of MRI, the incidence of childhood brain tumors seemed to rise in the 1980s, but has subsequently remained relatively stable. However, management of brain tumors in children has evolved substantially during this time, reflecting refinements in classification of tumors, delineation of risk groups within histological subsets of tumors, and incorporation of molecular techniques to further define tumor subgroups. Although considerable progress has been made in the outcomes of certain tumors, prognosis in other childhood brain tumor types is poor. Among the tumor groups with more-favorable outcomes, attention has been focused on reducing long-term morbidity without sacrificing survival rates. Studies for high-risk groups have examined the use of intensive therapy or novel, molecularly targeted approaches to improve disease control rates. In addition to reviewing the literature and providing an overview of the complexities in diagnosing childhood brain tumors, we will discuss advances in the treatment and categorization of several tumor types in which progress has been most apparent, as well as those in which improvements have been lacking. The latest insights from molecular correlative studies that hold potential for future refinements in therapy will also be discussed.

  13. Large gastrointestinal stromal tumor and advanced adenocarcinoma in the rectum coexistent with an incidental prostate carcinoma: A case report

    Directory of Open Access Journals (Sweden)

    Toshiaki Suzuki

    2014-01-01

    CONCLUSION: Radical surgery with perioperative adjuvant chemotherapy using tyrosine kinase inhibitors is the choice for treatment of large GISTs with a malignant potential. Our report suggests that aggressive surgical approach would be feasible, when a secondary tumor is present near the GIST.

  14. Early Evaluation of Response Using18F-FDG PET Influences Management in Gastrointestinal Stromal Tumor Patients Treated with Neoadjuvant Imatinib.

    Science.gov (United States)

    Farag, Sheima; Geus-Oei, Lioe-Fee de; van der Graaf, Winette T; van Coevorden, Frits; Grunhagen, Dirk; Reyners, Anna K L; Boonstra, Pieter A; Desar, Ingrid; Gelderblom, Hans; Steeghs, Neeltje

    2018-02-01

    18 F-FDG PET has previously been proven effective as an early way to evaluate the response of gastrointestinal stromal tumors (GISTs) to imatinib treatment. However, it is unclear whether early evaluation of response affects treatment decisions in GIST patients treated with neoadjuvant intent. Methods: We retrospectively scored changes in management based on early evaluation of response by 18 F-FDG PET in patients in the Dutch GIST registry treated with neoadjuvant imatinib. Results: Seventy 18 F-FDG PET scans were obtained for 63 GIST patients to evaluate for an early response to neoadjuvant imatinib. The scans led to a change in management in 27.1% of the patients. Change in management correlated strongly with lack of metabolic response ( P < 0.001) and non- KIT exon 11-mutated GISTs ( P < 0.001). Conclusion: Performing 18 F-FDG PET for early evaluation of response often results in a change of management in GIST patients harboring the non- KIT exon 11 mutation and should be considered the standard of care in GIST patients treated with neoadjuvant intent. © 2018 by the Society of Nuclear Medicine and Molecular Imaging.

  15. The value of (18) F-fluorodeoxyglucose positron emission tomography for prediction of treatment response in gastrointestinal stromal tumors: a systematic review and meta-analysis.

    Science.gov (United States)

    Hassanzadeh-Rad, Arman; Yousefifard, Mahmoud; Katal, Sanaz; Asady, Hadi; Fard-Esfahani, Armaghan; Moghadas Jafari, Ali; Hosseini, Mostafa

    2016-05-01

    Early detection of response to treatment is critically important in gastrointestinal stromal tumors (GIST). Therefore, the present systematic review and meta-analysis assessed the value of (18) f-fluorodeoxyglucose positron emission tomography ((18) FDG-PET) on prediction of therapeutic response of GIST patients to systemic treatments. The literature search was conducted using PubMed, SCOPUS, Cochrane, and Google Scholar databases, and review article references. Eligible articles were defined as studies included confirmed GIST patients who underwent (18) FDG-PET as well as assessing the screening role of it. Finally, 21 relevant articles were included. The analysis showed the pooled sensitivity and specificity of 18FDG-PET in evaluation of response to treatment of GIST patient were 0.90 (95% CI: 0.85-0.94; I(2)  = 52.59, P = 0.001) and 0.62 (95% CI: 0.49-0.75; I(2)  = 69.7, P = 0.001), respectively. In addition, the pooled prognostic odds ratio of (18) FDG-PET for was 14.99 (95% CI, 6.42-34.99; I(2)  = 100.0, P present meta-analysis showed (18) FDG-PET has a significant value in predicting treatment response in GIST patients. © 2015 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.

  16. Regorafenib for advanced gastrointestinal stromal tumors following imatinib and sunitinib treatment: a subgroup analysis evaluating Japanese patients in the phase III GRID trial.

    Science.gov (United States)

    Komatsu, Yoshito; Doi, Toshihiko; Sawaki, Akira; Kanda, Tatsuo; Yamada, Yasuhide; Kuss, Iris; Demetri, George D; Nishida, Toshirou

    2015-10-01

    The randomized, double-blind, placebo-controlled GRID trial tested the oral multikinase inhibitor regorafenib in 199 patients with advanced gastrointestinal stromal tumors (GIST) following failure of at least imatinib and sunitinib, and showed a significant improvement in progression-free survival (PFS) versus placebo [hazard ratio (HR) 0.27; 95 % confidence interval (CI) 0.19-0.39; p regorafenib 160 mg once daily with matching placebo, in combination with best supportive care. The primary study endpoint was progression-free survival (PFS); safety was evaluated through the incidence of adverse events (AEs). Seventeen Japanese patients were randomized to regorafenib (n = 12) or placebo (n = 5). Patient demographics were consistent with those of the overall study population. PFS was significantly longer with regorafenib than placebo (HR 0.08; 95 % CI 0.02-0.45; p = 0.000164). Centrally assessed disease control rates were 58 % and 20 % in the regorafenib and placebo groups, respectively (p = 0.080796). Treatment-related adverse events (AEs) were reported in all regorafenib-treated patients and 60 % of placebo recipients; the most frequent AE was hand-foot skin reaction (HFSR) (92 % versus 20 %, respectively). Regorafenib showed efficacy and a manageable safety profile in Japanese patients with advanced GIST, consistent with the overall GRID study population. AEs, such as HFSR and maculopapular rash, were observed more frequently in Japanese patients. Although dose modification was frequently reported, only one patient with hepatic failure discontinued regorafenib because of AEs.

  17. A phase I study of the HSP90 inhibitor retaspimycin hydrochloride (IPI-504) in patients with gastrointestinal stromal tumors or soft-tissue sarcomas.

    Science.gov (United States)

    Wagner, Andrew J; Chugh, Rashmi; Rosen, Lee S; Morgan, Jeffrey A; George, Suzanne; Gordon, Michael; Dunbar, Joi; Normant, Emmanuel; Grayzel, David; Demetri, George D

    2013-11-01

    Heat shock protein 90 (HSP90) is required for the proper folding, function, and stability of various client proteins, two of which (KIT and PDGFRα) are critical in the pathogenesis and progression of gastrointestinal stromal tumors (GIST). This phase I study investigated the safety and maximum tolerated dose (MTD) of retaspimycin hydrochloride (IPI-504), a novel potent and selective HSP90 inhibitor, in patients with metastatic and/or unresectable GIST or other soft-tissue sarcomas (STS). IPI-504 was administered intravenously at doses ranging from 90 to 500 mg/m(2) twice weekly for 2 weeks on/1 week off. Safety, pharmacokinetic, and pharmacodynamic profiles were determined. Response was assessed by Response Evaluation Criteria for Solid Tumors (RECIST) 1.0 and optionally via 18-fluorodeoxyglucose positron emission tomography (18-FDG-PET) imaging. Fifty-four patients received IPI-504; 37 with GIST and 17 with other STS. The MTD was 400 mg/m(2) twice weekly for 2 weeks on/1 week off. Common related adverse events were fatigue (59%), headache (44%), and nausea (43%). Exposure to IPI-504, 17-AAG, and 17-AG increased with IPI-504 dose. Stable disease (SD) was observed in 70% (26 of 37) of patients with GIST and 59% (10 of 17) of patients with STS. There was one confirmed partial response (PR) in a patient with GIST and one PR in a patient with liposarcoma. Metabolic partial responses occurred in 11 of 29 (38%) patients with GIST. In this study of advanced GIST or other STS, IPI-504 was generally well-tolerated with some evidence of antitumor activity, serving as a clinical proof-of-concept that HSP90 inhibition remains a promising strategy.

  18. Resveratrol suppresses migration, invasion and stemness of human breast cancer cells by interfering with tumor-stromal cross-talk.

    Science.gov (United States)

    Suh, Jinyoung; Kim, Do-Hee; Surh, Young-Joon

    2018-04-02

    Cancer-associated fibroblasts (CAFs) constitute a major compartment of the tumor microenvironment. CAFs produce a variety of cytokines, growth factors and extracellular matrix proteins, thereby stimulating tumor progression. CAFs are distinct from normal fibroblasts for their overexpression of α-smooth muscle actin. Recent studies suggest that CAFs play an important role in proliferation and migration of cancer cells through cross-talk with them. Resveratrol (trans-3,4'5,-trihydroxystilbene), a phytoalexin present in grapes, has been reported to possess chemopreventive and chemotherapeutic activities. In the present study, we examined the effects of resveratrol on CAF-induced migration, invasion and self-renewal activity of breast cancer cells. Resveratrol inhibited proliferation, migration and invasion of human breast cancer cells treated with CAF-conditioned media (CAF-CM). Resveratrol treatment suppressed the CAF-CM-induced expression of Cyclin D1, c-Myc, MMP-2 and MMP-9. In addition, resveratrol inhibited Sox2 expression as well as activation of Akt and STAT3 induced by CAF-CM in breast cancer cells. Further, resveratrol abrogated stemness properties and reduced the expression of self-renewal signaling molecules in stem-like breast cancer cells. Taken together, the present study provides insights into the role of resveratrol in tumor microenvironment with focus on interaction between cancer cells and the hosting niche. Copyright © 2018 Elsevier Inc. All rights reserved.

  19. Molecular pathogenesis of progression and recurrence in breast phyllodes tumors

    Science.gov (United States)

    Jara-Lazaro, Ana Richelia; Tan, Puay Hoon

    2009-01-01

    Breast phyllodes tumors are rare fibroepithelial neoplasms that need to be distinguished from the common morphologically similar fibroadenomas, because phyllodes tumors can recur and progress to malignancy. Their potentially recurring and metastasizing behavior is attributed to their stromal characteristics, for which categorization between benign, borderline and malignant tumors have not been universally established. Previous clonality studies revealing monoclonal stromal cells versus a polyclonal epithelial component theorized that phyllodes tumors are mainly stromal neoplasms, possibly arising from fibroadenomas. More recent chromosomal imbalances in both epithelium and stroma have challenged this theory to favor neoplasia of both epithelium and stroma, with initial interdependence between the two components. Inverse correlations between epithelial and stromal overexpression for various biological markers like estrogen receptor, p53, c-kit, Ki-67, endothelin-1, epidermal growth factor receptor, heparan sulfate, in addition to findings of epithelial Wnt signalling with stromal insulin growth factors and beta-catenin expression, suggest an initial epithelial-stromal interdependence at the benign phase. Upon progression to malignancy, the stroma is hypothesized to assume an autonomous growth overriding any epithelial influence. Frequent genetic alterations are chromosomal gains of 1q and losses at chromosome 13. Acquisition of new genetic imbalances within the tumor consistent with intratumoral heterogeneity, and subclones within histologically benign phyllodes tumors that recur or metastasize are the current theories explaining these tumors' unpredictable clinical behavior. PMID:19966935

  20. Identification of prognostic collagen signatures and potential therapeutic stromal targets in canine mammary gland carcinoma.

    Directory of Open Access Journals (Sweden)

    Ashley Case

    Full Text Available Increasing evidence indicates that the tumor microenvironment plays a critical role in regulating the biologic behavior of breast cancer. In veterinary oncology, there is a need for improved prognostic markers to accurately identify dogs at risk for local and distant (metastatic recurrence of mammary gland carcinoma and therefore would benefit from adjuvant therapy. Collagen density and fiber organization have been shown to regulate tumor progression in both mouse and human mammary tumors, with certain collagen signatures predicting poor outcomes in women with breast cancer. We hypothesized that collagen signatures in canine mammary tumor biopsies can serve as prognostic biomarkers and potential targets for treatment. We used second harmonic generation imaging to evaluate fibrillar collagen density, the presence of a tumor-stromal boundary, tumor associated collagen signatures (TACS and individual collagen fiber characteristics (width, length and straightness in grade I/II and grade III canine mammary tumors. Collagen density, as well as fiber width, length and straightness, were inversely correlated with patient overall survival time. Notably, grade III cases were less likely to have a tumor-stromal boundary and the lack of a boundary predicted poor outcome. Importantly, a lack of a defined tumor-stromal boundary and an increased collagen fiber width were associated with decreased survival even when tumor grade, patient stage, ovariohysterectomy status at the time of mammary tumor excision, and histologic evidence of lymphovascular invasion were considered in a multivariable model, indicating that these parameters could augment current methods to identify patients at high risk for local or metastatic progression/recurrence. Furthermore, these data, which identify for the first time, prognostic collagen biomarkers in naturally occurring mammary gland neoplasia in the dog, support the use of the dog as a translational model for tumor-stromal

  1. ACRIN 6665/RTOG 0132 phase II trial of neoadjuvant imatinib mesylate for operable malignant gastrointestinal stromal tumor: monitoring with 18F-FDG PET and correlation with genotype and GLUT4 expression.

    Science.gov (United States)

    Van den Abbeele, Annick D; Gatsonis, Constantine; de Vries, Daniel J; Melenevsky, Yulia; Szot-Barnes, Agnieszka; Yap, Jeffrey T; Godwin, Andrew K; Rink, Lori; Huang, Min; Blevins, Meridith; Sicks, Jorean; Eisenberg, Burton; Siegel, Barry A

    2012-04-01

    We investigated the correlation between metabolic response by (18)F-FDG PET and objective response, glucose transporter type 4 (GLUT4) expression, and KIT/PDGFRA mutation status in patients with gastrointestinal stromal tumor undergoing neoadjuvant imatinib mesylate therapy. (18)F-FDG PET was performed at baseline, 1-7 d, and 4 or 8 wk after imatinib mesylate initiation. Best objective response was defined by version 1.0 of the Response Evaluation Criteria in Solid Tumors (RECIST). Mutational analysis and tumor GLUT4 expression by immunohistochemistry were done on tissue obtained at baseline or surgery. (18)F-FDG PET showed high baseline tumor glycolytic activity (mean SUV(max), 14.2; range, 1.3-53.2), decreasing after 1 wk of imatinib mesylate (mean, 5.5; range, -0.5-47.7, P imatinib mesylate initiation, metabolic response by (18)F-FDG PET was documented earlier (1-7 d) and was of much greater magnitude (36/44) than that documented by RECIST (2/39). Immunohistochemistry data suggest that GLUT4 may play a role in (18)F-FDG uptake in gastrointestinal stromal tumor, GLUT4 levels decrease after imatinib mesylate therapy in most patients with PMR, and the biologic action of imatinib mesylate interacts with glycolysis and GLUT4 expression. A greater than 85% metabolic response was observed as early as days 1-7 in patients with exon 11 mutations.

  2. Current opinions on radiotherapy of pediatric central nervous system tumors

    International Nuclear Information System (INIS)

    Chojnacka, M.; Skowronska-Gardas, A.

    2006-01-01

    Primary central nervous system (CNS) neoplasms are the most frequent solid tumors in childhood accounting for 20% of all pediatric malignancies. Despite developments in neurosurgery, radiotherapy and chemotherapy, a significant proportion of these patients suffer progressive disease. A good treatment management strategy should consider not only survival but also the quality of life of the child. Irradiation is ann essential part of the management of the majority of CNS tumors. During then last decade, there significant advances in the technology of planning and delivery of radiation treatment. These new radiotherapy techniques such as conformal, intensity modulated photon beam and stereotactic methods allow a high homogenous dose to the tumor region with minimal doses to normal tissue. This is particularly important in children with localized low-grade tumors, whose prognosis of long-term survival is often excellent and should be accompanied by smallest risk of treatment toxicity. For small tumors fractionated radiotherapy stereotactic radiotherapy using multiple fixed non-coplanar beams is an appropriate treatment. Modification of craniospinal technique, lowering of the total craniospinal dose with adjuvant chemotherapy, new radiotherapy modalities to treat the posterior fossa may be employed to possibly decrease the late rectifies of radiation therapy. For malignant glioma and brain stem tumors we need new approaches, as chemo sensitization, angiogenesis inhibitors and gene therapies. These new methods in therapy of pediatric brain tumors and our experience in treatment of children with medulloblastoma, low-grade astrocytoma, craniopharyngioma and brain stem tumors are presented. We summarize therapeutic aspects of most childhood brain tumors. (author)

  3. Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumor after failure with imatinib and sunitinib treatment: A meta-analysis.

    Science.gov (United States)

    Zhang, Zhenan; Jiang, Tao; Wang, Wensheng; Piao, Daxun

    2017-12-01

    This meta-analysis aimed to evaluate the safety and efficacy of regorafenib as a treatment for patients with advanced (metastatic and/or unresectable) gastrointestinal stromal tumor (AGIST) after developing resistance to imatinib and sunitinib. A literature search of databases such as PubMed, Embase, and Cochrane library was conducted up to February 2017. The pooled percentages and the corresponding 95% confidence intervals (CIs) were calculated using the Stata 11.0 software. Four studies involving 243 patients with AGIST were included. Results revealed that approximately 49% (95% CI 30-67), 14% (95% CI 5-23), and 41% (95% CI 21-61) of patients with AGIST showed clinical benefit (including complete response), partial response, and stable disease, respectively, after regorafenib treatment, which was given after failure with imatinib and sunitinib treatments. No complete response was found in the included studies. Pooled progression-free survival was 6.58 months (95% CI 4.62-8.54). Hypertension (20%; 95% CI 7-33), hand-foot skin reaction (22%; 95% CI 17-27), and hypophosphatemia (18%; 95% CI 5-41) were common grade ≥3 regorafenib-related adverse events in patients treated with regorafenib after failure with imatinib and sunitinib treatments. Forty-nine per cent of patients with AGIST benefited after regorafenib treatment after the development of resistance to imatinib and sunitinib. More studies should be performed to improve the clinical survival of patients with AGIST. Close monitoring and appropriate management of grade ≥3 regorafenib-related adverse events should be considered during treatment.

  4. A phase II trial of regorafenib in patients with metastatic and/or a unresectable gastrointestinal stromal tumor harboring secondary mutations of exon 17.

    Science.gov (United States)

    Yeh, Chun-Nan; Chen, Ming-Huang; Chen, Yen-Yang; Yang, Ching-Yao; Yen, Chueh-Chuan; Tzen, Chin-Yuan; Chen, Li-Tzong; Chen, Jen-Shi

    2017-07-04

    Gastrointestinal stromal tumors (GISTs) are caused by the constitutive activation of KIT or platelet-derived growth factor receptor alpha (PDGFRA) mutations. Imatinib selectively inhibits KIT and PDGFR, leading to disease control for 80%-90% of patients with metastatic GIST. Imatinib resistance can occur within a median of 2-3 years due to secondary mutations in KIT. According to preclinical studies, both imatinib and sunitinib are ineffective against exon 17 mutations. However, the treatment efficacy of regorafenib for patients with GIST with exon 17 mutations is still unknown. Documented patients with GIST with exon 17 mutations were enrolled in this study. Patients received 160 mg of oral regorafenib daily on days 1-21 of a 28-day cycle. The primary end point of this trial was the clinical benefit rate (CBR; i.e., complete or partial response [PR], as well as stable disease [SD]) at 16 weeks. The secondary end points of this study included progression free survival (PFS), overall survival, and safety. Between June 2014 to May 2016, 18 patients were enrolled (15 of which were eligible for response evaluation). The CBR at 16 weeks was 93.3% (14 of 15; 6 PR and 8 SD). The median PFS was 22.1 months. The most common grade 3 toxicities were hand-and-foot skin reactions (10 of 18; 55.6%), followed by hypertension (5 of 18; 27.8%). Regorafenib significantly prolonged PFS in patients with advanced GIST harboring secondary mutations of exon 17. A phase III trial of regorafenib versus placebo is warranted. This trial is registered at ClinicalTrials.gov in November 2015, number NCT02606097.Key message: This phase II trial was conducted to assess the efficacy and safety of regorafenib in patients with GIST with exon 17 mutations. The results provide strong evidence that regorafenib significantly prolonged PFS in patients with advanced GIST harboring secondary mutations of exon 17.

  5. Gastrointestinal stromal tumor: analysis of 146 cases of the center of reference of the National Cancer Institute--INCA.

    Science.gov (United States)

    Linhares, Eduardo; Gonçalves, Rinaldo; Valadão, Marcus; Vilhena, Bruno; Herchenhorn, Daniel; Romano, Sergio; Ferreira, Maria Aparecida; Ferreira, Carlos Gil; Ramos, Cintia de Araujo; de Jesus, José Paulo

    2011-01-01

    To evaluate the treatment of GIST in INCA. We conducted a retrospective analysis of all cases of GIST treated at INCA in the period from 1997 to 2009. We analyzed 146 patients with a mean age of 44.5 years and female predominance. The main symptom was abdominal pain. We observed the occurrence of a second primary tumor in 22% of cases and 92% of the immunohistochemistry exams were positive for CD117. The most frequent location was in the stomach and the high-risk group was predominant. Surgery was considered R0 (extensive) in 70% of the cases and the main sites of metastases were liver and peritoneum. Overall survival in two and five years was, respectively, 86% and 59%. There was a significant difference between overall survival (p = 0.29) of the high-risk group versus the other. Our patients presented mainly in the form of high-risk disease, with obvious impact on survival. The use of imatinib improved survival of patients with recurrent and metastatic disease. We should study its use in the setting of adjuvant and neoadjuvant therapy to improve results of the high risk group. The creation of reference centers is a need for the study of rare diseases.

  6. Co-culture with bone marrow stromal cells protects PC12 neuronal cells from tumor necrosis factor-α-induced apoptosis by inhibiting the tumor necrosis factor receptor/caspase signaling pathway.

    Science.gov (United States)

    Li, Li; Wang, Jing; Tang, Ling; Yu, Xin; Sui, Yi; Zhang, Chaodong

    2015-07-01

    Bone marrow stromal cells (BMSCs), derived from the mesoderm, have been applied in the repair and reconstruction of injured tissues. The present study was conducted to explore the effects of BMSCs on cell viability of tumor necrosis factor-α (TNF-α)-stimulated PC12 cells. PC12 cells were co-cultured with BMSCs under TNF-α treatment, with normal PC12 cells as controls. Results from an MTT assay indicated that BMSCs significantly increased cell growth and proliferation of TNF-α-treated PC12 cells (survival rates were 56.71 and 76.86% for the positive control (PC) and co-culture group, respectively). Furthermore, Annexin V/propidium iodide staining and flow cytometric analysis demonstrated that TNF-α increased PC12-cell apoptosis from 3.49 to 40.74% in the negative control and PC group, and the apoptotic rate was significantly reduced upon co-culture with BMSCs to 16.97%. In addition, data from reverse transcription-quantitative polymerase chain reaction and western blot analyses illustrated that TNF-α-induced upregulation in TNF receptor (TNFR)-1 (TNFR1) and caspase-8 expression in PC12 cells were partially reversed by co-culture with BMSCs. In conclusion, the present study suggested that BMSCs protect PC12 cells against stimulation with TNF-α, which is partially mediated through the TNFR/caspase signaling pathway. The results of the present study also suggested a therapeutic use of BMSCs in clinical neurodegenerative diseases.

  7. Evidences of early senescence in multiple myeloma bone marrow mesenchymal stromal cells.

    Directory of Open Access Journals (Sweden)

    Thibaud André

    Full Text Available BACKGROUND: In multiple myeloma, bone marrow mesenchymal stromal cells support myeloma cell growth. Previous studies have suggested that direct and indirect interactions between malignant cells and bone marrow mesenchymal stromal cells result in constitutive abnormalities in the bone marrow mesenchymal stromal cells. DESIGN AND METHODS: The aims of this study were to investigate the constitutive abnormalities in myeloma bone marrow mesenchymal stromal cells and to evaluate the impact of new treatments. RESULTS: We demonstrated that myeloma bone marrow mesenchymal stromal cells have an increased expression of senescence-associated β-galactosidase, increased cell size, reduced proliferation capacity and characteristic expression of senescence-associated secretory profile members. We also observed a reduction in osteoblastogenic capacity and immunomodulatory activity and an increase in hematopoietic support capacity. Finally, we determined that current treatments were able to partially reduce some abnormalities in secreted factors, proliferation and osteoblastogenesis. CONCLUSIONS: We showed that myeloma bone marrow mesenchymal stromal cells have an early senescent profile with profound alterations in their characteristics. This senescent state most likely participates in disease progression and relapse by altering the tumor microenvironment.

  8. Local anesthetics for brain tumor resection: Current perspectives

    NARCIS (Netherlands)

    J.W. Potters (Jan Willem); M. Klimek (Markus)

    2018-01-01

    textabstractThis review summarizes the added value of local anesthetics in patients undergoing craniotomy for brain tumor resection, which is a procedure that is carried out frequently in neurosurgical practice. The procedure can be carried out under general anesthesia, sedation with local

  9. Morphology of gastrointestinal stromal tumors in advanced stages of the disease: baseline findings before chemotherapy with imatinib; Morphologie gastrointestinaler Stromatumoren im fortgeschrittenen Stadium der Erkrankung: Ausgangsbefunde vor Chemotherapie mit Imatinib

    Energy Technology Data Exchange (ETDEWEB)

    Jost, D.; Strosczynski, C.; Chmelik, P.; Gaffke, G.; Schlecht, I.; Felix, R. [Humboldt-Universitaet, Berlin (Germany). Universitaetsklinikum Charite, Klinik und Poliklinik fuer Strahlenheilkunde; Pink, D.; Reichardt, P. [Humboldt-Universitaet, Berlin (Germany). Universitaetsklinikum Charite, Klinik fuer Haematologie, Onkologie und Tumorimmunologie; Schneider, U. [Humboldt-Universitaet, Berlin (Germany). Universitaetsklinikum Charite, Inst. fuer Pathologie; Hohenberger, P. [Humboldt-Universitaet, Berlin (Germany). Universitaetsklinikum Charite, Klinik fuer Chirurgie und Chirurgische Onkologie

    2003-06-01

    Purpose: Gastrointestinal stromal tumors (GISTs) are rare tumors of the gastrointestinal tract with an increasing detection rate due to improved differentiating methods in current diagnostic pathology. This study evaluates the radiologic characteristics of these neoplasms to discover specific signs leading to an earlier diagnosis. Materials and Methods: As part of a randomized phase III clinical trial of the European Organization for Research and Treatment of Cancer (EORTC), 72 patients with advanced stage GIST were treated with the selective tyrosine-kinase-inhibitor imatinib (Glivec {sup trademark}, Novartis, Switzerland). For initial staging, 60 patients underwent MRI and 12 patients underwent CT. Results: GISTs are mesenchymal tumors that grow submucosally and exophytically and become multiple, nodular or ovoid in the advanced stage. The predominant findings are peripheral solid structures with strong contrast enhancement and a central necrosis. Metastases are primarily located in the liver, where they appear as oval or round, sharply delineated solitary lesions with central necrosis. CT demonstrates the primary tumors and local recurrences as nearly isodense with the liver. On MRI, the lesions are hypointense on T{sub 1}-weighted sequences and hyperintense on T{sub 2}-weighted sequences, compared to the liver. Conclusion: Immunopathology now enables the exact histologic separation of GISTs from other mesenchymal tumors. The radiological morphology is not sufficiently specific to differentiate GISTs from other mesenchymal tumors. In view of new therapeutic options, cognizance of their typical manifestations is of increasing importance for radiologists. (orig.) [German] Ziel: Gastrointestinale Stromatumoren (GIST) sind seltene Tumoren des Gastrointestinaltraktes. Bedingt durch neue Differenzierungsmethoden in der pathologischen Diagnostik wird die Detektionsrate ansteigen. Ziel dieser Studie ist die Evaluation spezifischer radiologischer Kriterien, die in der

  10. Gastric Cancer and Gastrointestinal Stromal Tumors Could be Causes of non-Helicobacter Pylori non-NSAIDs Peptic Ulcers in Thailand

    Science.gov (United States)

    Kiatpapan, Pattama; Vilaichone, Ratha korn; Chotivitayatarakorn, Peranart; Mahachai, Varocha

    2017-01-01

    Background and aim: H. pylori and nonsteroidal anti-inflammatory drugs (NSAIDs) remain the major causes of peptic ulcer disease. Nevertheless, non- H. pylori non-NSAIDs peptic ulcers or idiopathic peptic ulcer disease (IPUD) constitute a growing problem associated with many complications. Gastric cancer and gastrointestinal stromal tumor (GIST) have also been reported as a cause of IPUD. This study was aimed to investigate prevalence and clinical characteristics of IPUD in Thailand. Materials and Methods: Clinical information, histological features, endoscopic findings, history of H. pylori status and NSAIDs usage were collected for patients diagnosed with PUD in Thammasat University Hospital during January 2003 – December 2013. Results: Total of 1,310 patients was diagnosed with PUD in our institution during the study period, of which 71 (5.4%) had a definitive diagnosis of IPUD (45 men and 26 women, mean age of 59±16.5 years). Common locations were gastric antrum (43.7%), duodenum (25.3%) and gastric body (12.7%). Common causes of IPUD were idiopathic (43.7%) and alcohol consumption (39.4%). Gastric cancer and GIST were also demonstrated in 1(1.4%) and 1(1.4%) respectively. Major complications were upper GI bleeding (73.2%) and peptic perforation (2.8%). Recurrent upper GI bleeding was detected in 23.9%. Interestingly, male patients aged<50 years with alcohol related peptic ulcer were significantly more common than female patients aged ≥ 50 years (57.8% vs 7.7%;P-value= 0.00002, OR= 16.4, 95%CI= 3.5-78 and 68.4% vs 28.9%); P-value= 0.002, OR= 5.3, 95% CI= 1.7-16.7). Conclusion: Common causes of IPUD in Thailand are idiopathic followed by alcohol consumption and steroid usage. Gastric cancer and GIST are also possible causes of IPUD. These particular ulcers had a high likelihood of developing severe complications. Appropriate screening and high level of suspicion of fatal causes eg. gastric cancer and GIST should be appropriate ways to reduce complications

  11. Local anesthetics for brain tumor resection: current perspectives

    Science.gov (United States)

    Potters, Jan-Willem

    2018-01-01

    This review summarizes the added value of local anesthetics in patients undergoing craniotomy for brain tumor resection, which is a procedure that is carried out frequently in neurosurgical practice. The procedure can be carried out under general anesthesia, sedation with local anesthesia or under local anesthesia only. Literature shows a large variation in the postoperative pain intensity ranging from no postoperative analgesia requirement in two-thirds of the patients up to a rate of 96% of the patients suffering from severe postoperative pain. The only identified causative factor predicting higher postoperative pain scores is infratentorial surgery. Postoperative analgesia can be achieved with multimodal pain management where local anesthesia is associated with lower postoperative pain intensity, reduction in opioid requirement and prevention of development of chronic pain. In awake craniotomy patients, sufficient local anesthesia is a cornerstone of the procedure. An awake craniotomy and brain tumor resection can be carried out completely under local anesthesia only. However, the use of sedative drugs is common to improve patient comfort during craniotomy and closure. Local anesthesia for craniotomy can be performed by directly blocking the six different nerves that provide the sensory innervation of the scalp, or by local infiltration of the surgical site and the placement of the pins of the Mayfield clamp. Direct nerve block has potential complications and pitfalls and is technically more challenging, but mostly requires lower total doses of the local anesthetics than the doses required in surgical-site infiltration. Due to a lack of comparative studies, there is no evidence showing superiority of one technique versus the other. Besides the use of other local anesthetics for analgesia, intravenous lidocaine administration has proven to be a safe and effective method in the prevention of coughing during emergence from general anesthesia and extubation, which

  12. The current status and clinical value of circulating tumor cells and circulating cell-free tumor DNA in bladder cancer.

    Science.gov (United States)

    Riethdorf, Sabine; Soave, Armin; Rink, Michael

    2017-12-01

    Urothelial carcinoma of the bladder (UCB) is a complex disease, which is associated with highly aggressive tumor biologic behavior, especially in patients with muscle-invasive and advanced tumors. Despite multimodal therapy options including surgery, radiotherapy and chemotherapy, UCB patients frequently suffer from poor clinical outcome. Indeed, the potential of diverse opportunities for modern targeted therapies is not sufficiently elucidated in UCB yet. To improve the suboptimal treatment situation in UCB, biomarkers are urgently needed that help detecting minimal residual disease (MRD), predicting therapy response and subsequently prognosis as well as enabling patient stratification for further therapies and therapy monitoring, respectively. To date, decision making regarding treatment planning is mainly based on histopathologic evaluation of biopsies predominantly derived from the primary tumors and on clinical staging. However, both methods are imperfect for sufficient outcome prediction. During disease progression, individual disseminated tumor cells and consecutively metastases can acquire characteristics that do not match those of the corresponding primary tumors, and often are only hardly assessable for further evaluation. Therefore, during recent years, strong efforts were directed to establish non-invasive biomarkers from liquid biopsies. Urine cytology and serum tumor markers have been established for diagnostic purposes, but are still insufficient as universal biomarkers for decision-making and treatment of UCB patients. To date, the clinical relevance of various newly established blood-based biomarkers comprising circulating tumor cells (CTCs), circulating cell-free nucleic acids or tumor-educated platelets is being tested in cancer patients. In this review we summarize the current state and clinical application of CTCs and circulating cell-free tumor DNA originating from blood as biomarkers in patients with different UCB stages.

  13. The current status and clinical value of circulating tumor cells and circulating cell-free tumor DNA in bladder cancer

    Science.gov (United States)

    Soave, Armin; Rink, Michael

    2017-01-01

    Urothelial carcinoma of the bladder (UCB) is a complex disease, which is associated with highly aggressive tumor biologic behavior, especially in patients with muscle-invasive and advanced tumors. Despite multimodal therapy options including surgery, radiotherapy and chemotherapy, UCB patients frequently suffer from poor clinical outcome. Indeed, the potential of diverse opportunities for modern targeted therapies is not sufficiently elucidated in UCB yet. To improve the suboptimal treatment situation in UCB, biomarkers are urgently needed that help detecting minimal residual disease (MRD), predicting therapy response and subsequently prognosis as well as enabling patient stratification for further therapies and therapy monitoring, respectively. To date, decision making regarding treatment planning is mainly based on histopathologic evaluation of biopsies predominantly derived from the primary tumors and on clinical staging. However, both methods are imperfect for sufficient outcome prediction. During disease progression, individual disseminated tumor cells and consecutively metastases can acquire characteristics that do not match those of the corresponding primary tumors, and often are only hardly assessable for further evaluation. Therefore, during recent years, strong efforts were directed to establish non-invasive biomarkers from liquid biopsies. Urine cytology and serum tumor markers have been established for diagnostic purposes, but are still insufficient as universal biomarkers for decision-making and treatment of UCB patients. To date, the clinical relevance of various newly established blood-based biomarkers comprising circulating tumor cells (CTCs), circulating cell-free nucleic acids or tumor-educated platelets is being tested in cancer patients. In this review we summarize the current state and clinical application of CTCs and circulating cell-free tumor DNA originating from blood as biomarkers in patients with different UCB stages. PMID:29354496

  14. Rare and Challenging Tumor Entity: Phyllodes Tumor of the Prostate

    Directory of Open Access Journals (Sweden)

    Andreas Bannowsky

    2009-01-01

    Full Text Available Cystic epithelial-stromal tumors of the prostate are rare, with 82 cases reported in literature. These cases have been published under a variety of diagnoses, including phyllodes tumor and prostatic stromal proliferation of uncertain malignant potential as well as a malignant tumor called “prostatic stromal sarcoma”. We report a case of a 60-year-old man with the histological diagnosis of phyllodes tumor of the prostate in transurethral resection specimen.

  15. Tumorer

    DEFF Research Database (Denmark)

    Prause, J.U.; Heegaard, S.

    2005-01-01

    oftalmologi, øjenlågstumorer, conjunctivale tumorer, malignt melanom, retinoblastom, orbitale tumorer......oftalmologi, øjenlågstumorer, conjunctivale tumorer, malignt melanom, retinoblastom, orbitale tumorer...

  16. Adipose-derived stem and stromal cells for cell-based therapy: current status of preclinical studies and clinical trials.

    Science.gov (United States)

    Mizuno, Hiroshi

    2010-08-01

    The potential use of stem cell-based therapies for the repair and regeneration of various tissues and organs offers a paradigm shift that may provide alternative therapeutic solutions for several diseases. The clinical use of either embryonic stem cells or induced pluripotent stem cells remains limited because of cell regulations, ethical considerations and the requirement for genetic manipulation, although these cells are theoretically highly beneficial. Adipose-derived stem cells (ASCs) appear to be an ideal population of stem cells for practical regenerative medicine, given that they are plentiful, of autologous tissue origin and thus non-immunogenic, and are more easily available because of minimal ethical considerations. Although ASCs originate from mesodermal lineages, recent preclinical studies have demonstrated that the use of ASCs in regenerative medicine is not limited to mesodermal tissue, but can also extend to both exodermal and endodermal tissues and organs. This review summarizes and discusses current preclinical and clinical data on the use of ASCs in regenerative medicine and discusses the future applications of such cell-based therapies.

  17. Brain tumor radiosurgery. Current status and strategies to enhance the effect of radiosurgery

    Energy Technology Data Exchange (ETDEWEB)

    Niranjan, A.; Lunsford, L.D.; Gobbel, G.T.; Kondziolka, D.; Maitz, A.; Flickinger, J.C. [Univ. of Pittsburgh Medical Center, PA (United States)

    2000-07-01

    First, the current status of brain tumor radiosurgery is reviewed, and radiosurgery for brain tumors, including benign tumors, malignant tumors, primary glial tumors, and metastatic tumors, is described. Rapid developments in neuroimaging, stereotactic techniques, and robotic technology in the last decade have contributed to improved results and wider applications of radiosurgery. Radiosurgery has become the preferred management modality for many intracranial tumors, including schwannomas, meningiomas, and metastatic tumors. Although radiosurgery provides survival benefits in patients with diffuse malignant brain tumors, cure is still not possible. Microscopic tumor infiltration into surrounding normal tissue is the main cause of recurrence. Additional strategies are needed to specifically target tumor cells. Next, strategies to enhance the effect of radiosurgery are reviewed. Whereas the long-term clinical results of radiosurgery have established its role in the treatment of benign tumors, additional strategies are needed to improve cell killing in malignant brain tumors and to protect normal surrounding brain. The first strategy included the use of various agents to protect normal brain while delivering a high dose to the tumor cells, but finding an effective radioprotective agent has been problematic. Pentobarbital and 21-aminosteroid (21-AS) are presented as examples. The second strategy for radiation protection aimed at the repair of radiation-induced damage to the normal brain. The cause of radiation-induced breakdown of normal tissue is unclear. The white matter and the cerebral vasculature appear to be particularly susceptible to radiation. Oligodendrocytes and endothelial cells may be critical targets of radiation. The authors hypothesize that radiation-induced damage to these cell types can be repaired by neural stem cells. They also describe the use of tumor necrosis factor alpha (TNF-alpha) and neural stem cells as a means of enhancing the effect of

  18. Interferon-gamma and tumor necrosis factor-alpha sensitize primarily resistant human endometrial stromal cells to Fas-mediated apoptosis

    DEFF Research Database (Denmark)

    Fluhr, Herbert; Krenzer, Stefanie; Stein, Gerburg M

    2007-01-01

    of Fas by an agonistic anti-Fas antibody. Incubation of ESCs with the early embryonic signal human chorionic gonadotropin (hCG, CGB) does not influence their reaction to Fas stimulation. The sensitizing effect of IFN-gamma and TNF-alpha was accompanied by a significant upregulation of Fas and FLICE......The subtle interaction between the implanting embryo and the maternal endometrium plays a pivotal role during the process of implantation. Human endometrial stromal cells (ESCs) express Fas and the implanting trophoblast cells secrete Fas ligand (FASLG, FasL), suggesting a possible role for Fas...

  19. Radiotherapy for pediatric brain tumors: Standard of care, current clinical trials, and new directions

    International Nuclear Information System (INIS)

    Kun, Larry E.

    1996-01-01

    Objectives: To review the clinical characteristics of childhood brain tumors, including neurologic signs, neuroimaging and neuropathology. To critically assess indications for therapy relevant to presenting characteristics, age, and disease status. To discuss current management strategies including neurosurgery, radiation therapy, and chemotherapy. To analyze current clinical trials and future directions of clinical research. Brain tumors account for 20% of neoplastic diseases in children. The most common tumors include astrocytoma and malignant gliomas, medulloblastoma and supratentorial PNET's, ependymoma, craniopharyngioma, and intracranial germ cell tumors. Tumor type and clinical course are often correlated with age at presentation and anatomic site. The clinical characteristics and disease extent largely determine the relative merits of available 'standard' and investigational therapeutic approaches. Treatment outcome, including disease control and functional integrity, is dependent upon age at presentation, tumor type, and disease extent. An understanding of the clinical, neuroimaging, and histologic characteristics as they relate to decisions regarding therapy is critical to the radiation oncologist. Appropriate radiation therapy is central to curative therapy for a majority of pediatric brain tumor presentations. Technical advances in neurosurgery provide greater safety for 'gross total resection' in a majority of hemispheric astrocytomas and medulloblastomas. The relative roles of 'standard' radiation therapy and evolving chemotherapy for centrally located astrocytomas (e.g., diencephalic, optic pathway) need to be analyzed in the context of initial and overall disease control, neurotoxicities, and potential modifications in the risk:benefit ratio apparent in the introduction of precision radiation techniques. Modifications in radiation delivery are fundamental to current investigations in medulloblastoma; the rationale for contemporary and projected

  20. Radiotherapy for pediatric brain tumors: Standard of care, current clinical trials and new directions

    International Nuclear Information System (INIS)

    Kun, Larry E.

    1997-01-01

    Objectives: To review the clinical characteristics of childhood brain tumors, including neurologic signs, neuroimaging and neuropathology. To critically assess indications for therapy relevant to presenting characteristics, age, and disease status. To discuss current management strategies including neurosurgery, radiation therapy, and chemotherapy. To analyze current clinical trials and future directions of clinical research. Brain tumors account for 20% of neoplastic diseases in children. The most common tumors include astrocytoma and malignant gliomas, medulloblastoma and supratentorial PNET's, ependymoma, craniopharyngioma, and intracranial germ cell tumors. The clinical characteristics and disease extent largely determine the relative merits of available 'standard' and investigational therapeutic approaches. Treatment outcome, including disease control and functional integrity, is dependent upon tumor type and site, age at presentation, and disease extent. An understanding of the clinical, neuroimaging, and histologic characteristics as they relate to decisions regarding therapy is critical to the radiation oncologist. Appropriate radiation therapy is central to curative therapy for a majority of pediatric brain tumor presentations. Technical advances in neurosurgery provide greater safety for 'gross total resection' in a majority of hemispheric astrocytomas and medulloblastomas. The relative roles of radiation therapy and chemotherapy for centrally located astrocytomas (e.g., diencephalic, optic pathway) need to be analyzed in the context of initial and overall disease control, neurotoxicities, and potential modifications in the risk:benefit ratio apparent in the introduction of 3-dimensional radiation techniques. Modifications in radiation delivery are important components of current investigations in medulloblastoma; the rationale for contemporary cooperative group trials will be presented as well as the background data re surgical, radiotherapeutic, and

  1. Maintaining Tumor Heterogeneity in Patient-Derived Tumor Xenografts.

    Science.gov (United States)

    Cassidy, John W; Caldas, Carlos; Bruna, Alejandra

    2015-08-01

    Preclinical models often fail to capture the diverse heterogeneity of human malignancies and as such lack clinical predictive power. Patient-derived tumor xenografts (PDX) have emerged as a powerful technology: capable of retaining the molecular heterogeneity of their originating sample. However, heterogeneity within a tumor is governed by both cell-autonomous (e.g., genetic and epigenetic heterogeneity) and non-cell-autonomous (e.g., stromal heterogeneity) drivers. Although PDXs can largely recapitulate the polygenomic architecture of human tumors, they do not fully account for heterogeneity in the tumor microenvironment. Hence, these models have substantial utility in basic and translational research in cancer biology; however, study of stromal or immune drivers of malignant progression may be limited. Similarly, PDX models offer the ability to conduct patient-specific in vivo and ex vivo drug screens, but stromal contributions to treatment responses may be under-represented. This review discusses the sources and consequences of intratumor heterogeneity and how these are recapitulated in the PDX model. Limitations of the current generation of PDXs are discussed and strategies to improve several aspects of the model with respect to preserving heterogeneity are proposed. ©2015 American Association for Cancer Research.

  2. Expression of osteoprotegerin, receptor activator of nuclear factor kappa-B ligand, tumor necrosis factor-related apoptosis-inducing ligand, stromal cell-derived factor-1 and their receptors in epithelial metastatic breast cancer cell lines

    Directory of Open Access Journals (Sweden)

    Labovsky Vivian

    2012-06-01

    Full Text Available Abstract Background While breast cancer (BC is the major cause of death among women worldwide, there is no guarantee of better patient survival because many of these patients develop primarily metastases, despite efforts to detect it in its early stages. Bone metastasis is a common complication that occurs in 65-80 % of patients with disseminated disease, but the molecular basis underlying dormancy, dissemination and establishment of metastasis is not understood. Our objective has been to evaluate simultaneously osteoprotegerin (OPG, receptor activator of nuclear factor kappa B ligand (RANKL, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL, stromal cell-derived factor-1 (SDF-1, and their receptors (R in 2 human BC cell lines, MDA-MB-231 and MCF-7. Methods OPG, RANKL, TRAIL and SDF-1 expression and release, in addition to the expression of their receptors has been investigated using immunofluorescence, immunocytochemistry and ELISA analyses. Results MCF-7 cells released higher levels of OPG in conditioned media (CM than MDA-MB-231 cells; 100 % of both types of cell expressed OPG, RANKL, TRAIL and SDF-1. Moreover, 100 % in both lines expressed membrane RANKL and RANK, whereas only 50 % expressed CXCR4. Furthermore, 100 % expressed TRAIL-R1 and R4, 30-50 % TRAIL-R2, and 40-55 % TRAIL-R3. Conclusions MCF-7 and MDA-MB-231 cells not only released OPG, but expressed RANKL, TRAIL and SDF-1. The majority of the cells also expressed RANK, CXCR4 and TRAIL-R. Since these ligands and their receptors are implicated in the regulation of proliferation, survival, migration and future bone metastasis during breast tumor progression, assessment of these molecules in tumor biopsies of BC patients could be useful in identifying patients with more aggressive tumors that are also at risk of bone metastasis, which may thus improve the available options for therapeutic intervention.

  3. Stroma Cells in Tumor Microenvironment and Breast Cancer

    Science.gov (United States)

    Mao, Yan; Keller, Evan T.; Garfield, David H.; Shen, Kunwei; Wang, Jianhua

    2015-01-01

    Cancer is a systemic disease, encompassing multiple components of both tumor cells themselves and host stromal cells. It is now clear that stromal cells in the tumor microenvironment play an important role in cancer development. Molecular events through which reactive stromal cells affect cancer cells can be defined so that biomarkers and therapeutic targets can be identified. Cancer-associated fibroblasts (CAFs) make up the bulk of cancer stroma and affect the tumor microenvironment such that they promote cancer initiation, angiogenesis, invasion and metastasis. In breast cancer, CAFs not only promote tumor progression, but also induce therapeutic resistances. Accordingly, targeting CAFs provides a novel way to control tumors with therapeutic resistances. This review summarizes the current understanding of tumor stroma in breast cancer with a particular emphasis on the role of CAFs and the therapeutic implications of CAFs. The effects of other stromal components such as endothelial cells, macrophages and adipocytes in breast cancer are also discussed. Finally, we describe the biologic markers to sort patients into a specific and confirmed subtype for personalized treatment. PMID:23114846

  4. Current role of selective internal radiation with yttrium-90 in liver tumors.

    Science.gov (United States)

    Lau, Wan Yee; Teoh, Yee Leong; Win, Khin Maung; Lee, Rheun-Chuan; de Villa, Vanessa H; Kim, Yun Hwan Joseph; Liang, Po-Chin; Santos-Ocampo, Ramon S; Lo, Richard Hoau Gong; Lim, Kieron Boon Leng; Tai, David Wai Meng; Ng, David Chee Eng; Irani, Farah Gillan; Gogna, Apoorva; Chow, Pierce Kah-Hoe

    2016-05-01

    An expert panel met to review the evidence for selective internal radiation therapy (SIRT) using yttrium-90 microspheres in hepatocellular carcinoma and metastases from colorectal cancer and neuroendocrine tumors. There is now convincing evidence for the safety and efficacy of SIRT in these situations albeit mostly from retrospective cohort studies. There are a number of ongoing prospective randomized controlled clinical trials investigating the role of SIRT in liver tumors; however, data from these trials are still several years away (although the SIRFLOX study has been recently published). In this evolving environment, published evidence and the authors' experience were used to summarize the current and potential role of SIRT in the management of hepatocellular carcinoma of intermediate or advanced stage and in liver-dominant metastatic colorectal cancer and metastatic neuroendocrine tumors.

  5. Activity of dasatinib, a dual SRC/ABL kinase inhibitor, and IPI-504, a heat shock protein 90 inhibitor, against gastrointestinal stromal tumor-associated PDGFRAD842V mutation.

    Science.gov (United States)

    Dewaele, Barbara; Wasag, Bartosz; Cools, Jan; Sciot, Raf; Prenen, Hans; Vandenberghe, Peter; Wozniak, Agnieszka; Schöffski, Patrick; Marynen, Peter; Debiec-Rychter, Maria

    2008-09-15

    Activating mutations in platelet-derived growth factor receptor-alpha (PDGFRA) have been reported in approximately 5% to 10% of patients with gastrointestinal stromal tumors (GIST). Imatinib efficiently inhibits the juxtamembrane PDGFRA mutations, whereas many tyrosine kinase domain activation loop PDGFRA mutations confer primary resistance to imatinib. In this study, we compared the efficacy of second-line tyrosine kinase inhibitors such as dasatinib, sorafenib, and nilotinib against two GIST-related PDGFRA mutants, PDGFRA(D842V) and PDGFRA(DeltaDIM842-844). In addition, we sought to investigate the inhibitory effect of the heat shock protein 90 inhibitor, IPI-504, on these mutants. Primary imatinib-resistant tumor cells and cell lines expressing imatinib-resistant PDGFRA(D842V) or imatinib-sensitive PDGFRA(DeltaDIM842-844) mutants were treated with different concentrations of dasatinib, sorafenib, nilotinib, and IPI-504. The effect of treatment on proliferation, survival, and signaling was determined. All inhibitors tested exhibited a high efficacy toward the PDGFRA(DeltaDIM842-844) mutant. In contrast, ex vivo and in vitro assays revealed that only dasatinib potently inhibited the PDGFRA(D842V) isoform with an IC(50) value of 62 nmol/L. Sorafenib and nilotinib were significantly less efficacious against this mutation, inhibiting the PDGFRA kinase activity at >1,000 and >5,000 nmol/L, and suppressing the proliferation of the cells expressing the PDGFRA(D842V) mutant with an IC(50) value of 239 and 1,310 nmol/L, respectively. IPI-504 treatment potently inhibited PDGFRA kinase activity by inducing the degradation of PDGFRA(D842V) and PDGFRA(DeltaDIM842-844) at 256 and 182 nmol/L, respectively. Treatment with dasatinib or the heat shock protein 90 inhibitor IPI-504 may provide a therapeutic alternative for GIST patients whose tumors carry the imatinib-resistant PDGFRA(D842V) mutant isoform.

  6. Myeloid-Derived Suppressor Cells in the Tumor Microenvironment: Current Knowledge and Future Perspectives.

    Science.gov (United States)

    Ibáñez-Vea, Maria; Zuazo, Miren; Gato, Maria; Arasanz, Hugo; Fernández-Hinojal, Gonzalo; Escors, David; Kochan, Grazyna

    2018-04-01

    The current knowledge on tumor-infiltrating myeloid-derived suppressor cells (MDSCs) is based mainly on the extensive work performed in murine models. Data obtained for human counterparts are generated on the basis of tumor analysis from patient samples. Both sources of information led to determination of the main suppressive mechanisms used by these cell subsets in tumor-bearing hosts. As a result of the identification of protein targets responsible for MDSCs suppressive activity, different therapeutics agents have been used to eliminate/reduce their adverse effect. In the present work, we review the current knowledge on suppressive mechanisms of MDSCs and therapeutic treatments that interfere with their differentiation, expansion or activity. Based on the accumulation of new evidences supporting their importance for tumor progression and metastasis, the interest in these cell types is increasing. We revise the methods of MDSC generation/differentiation ex vivo that may help in overcoming problems associated with limited numbers of cells available from animals and patients for their study.

  7. Bone Abnormalities in Mice with Protein Kinase A (PKA) Defects Reveal a Role of Cyclic AMP Signaling in Bone Stromal Cell-Dependent Tumor Development.

    Science.gov (United States)

    Liu, S; Shapiro, J M; Saloustros, E; Stratakis, C A

    2016-11-01

    Protein kinase A (PKA) is an important enzyme for all eukaryotic cells. PKA phosphorylates other proteins, thus, it is essential for the regulation of many diverse cellular functions, including cytoplasmic trafficking and signaling, organelle structure and mitochondrial oxidation, nuclear gene expression, the cell cycle, and cellular division. The PKA holoenzyme is composed of 2 regulatory and 2 catalytic subunits. Four regulatory (R1α, R1β, R2α, and R2β) and 4 catalytic subunits (Cα, Cβ, Cγ, and Prkx) have been identified, giving rise to mainly PKA-I (when the 2 regulatory subunits are either R1α or R1β), or PKA-II (when the 2 regulatory subunits are either R2α or R2β). Mutations in the PKA subunits can lead to altered total PKA activity or abnormal PKA-I to PKA-II ratio, leading to various abnormalities in both humans and mice. These effects can be tissue-specific. We studied the effect of PKA subunit defects on PKA activity and bone morphology of mice that were single or double heterozygous for null alleles of the various PKA subunit genes. Bone lesions including fibrous dysplasia, myxomas, osteo-sarcomas, -chondromas and -chondrosarcomas were found in these mice. Observational and molecular studies showed that these lesions were derived from bone stromal cells (BSCs). We conclude that haploinsufficiency for different PKA subunit genes affected bone lesion formation, new bone generation, organization, and mineralization in variable ways. This work identified a PKA subunit- and activity-dependent pathway of bone lesion formation from BSCs with important implications for understanding how cyclic AMP affects the skeleton and its tumorigenesis. © Georg Thieme Verlag KG Stuttgart · New York.

  8. MiR-125b inhibits stromal cell proliferation in giant cell tumor of bone by targeting parathyroid hormone 1 receptor

    Directory of Open Access Journals (Sweden)

    Pan-Feng Wu

    2015-07-01

    Conclusion:Our results suggest that miR-125b acts as a tumor suppressor through suppression of the PTH1R/RANKL signaling pathway. These findings contribute to our understanding of the functions of miR-125b in GCT.

  9. Radiotherapy confined to the tumor bed following breast conserving surgery. Current status, controversies, and future prospects

    Energy Technology Data Exchange (ETDEWEB)

    Polgar, C.; Fodor, J.; Major, T.; Takacsi-Nagy, Z.; Nemeth, G. [National Institut of Oncology, Department of Radiotherapy, Budapest (Hungary); Kasler, M. [Semmelweis University Budapest, Chair of Oncology, Budapest (Hungary); Hammer, J. [Barmherzige Schwestern Hospital, Department of Radiation Oncology, Linz (Austria); Limbergen, E. van [University Ziekenhuizen, Department of Radiation Oncology, Leuven (Belgium)

    2002-11-01

    The aim of this study was to review the current status, controversies, and future prospects of tumor bed irradiation alone after breast conserving surgery. Material and Methods: Published prospective trials evaluating the feasibility and efficacy of radiotherapy confined to the tumor bed following breast conserving surgery were reviewed in order to analyze treatment results. Results: In three earlier studies, using tumor bed radiotherapy for unselected patients, the incidence of intra-breast relapse was reported in the range of 15.6-37%. However, in nine prospective phase I-II trials, sole brachytherapy (BT) with different dose rates, strict patients selection, and meticulous quality assurance, resulted in 95.6-100% local control rates. To date, only one phase III protocol has been initiated comparing the efficacy of tumor bed brachytherapy alone with conventional whole breast radiotherapy. The ideal extent of the planning target volume (PTV) for tumor bed radiotherapy alone has not been established yet. In most series, PTV was defined as the excision cavity with generous (1-3 cm) safety margins. Minimal requirement for PTV localization is the use of titanium clips to mark the walls of the excision cavity intraoperatively, but the combination of clip demarcation and three-dimensional (3-D) visual information obtained from cross-sectional images seems to be the best method to determine the target volume. 3-D virtual brachytherapy is also a promising method to minimize the chance of geographic miss. Recently developed techniques, such as intraoperative radiotherapy (IORT), as well as accelerated 3-D conformal external beam radiation therapy (3-D-CRT) were also found to be feasible for tumor bed radiotherapy alone. Conclusions: In spite of the existing arguments against limiting radiotherapy to the tumor bed after breast conserving surgery, results of phase I-II studies suggest that tumor bed radiotherapy alone might be an appropriate treatment option for selected

  10. Stromal SPOCK1 supports invasive pancreatic cancer growth

    NARCIS (Netherlands)

    Veenstra, Veronique L.; Damhofer, Helene; Waasdorp, Cynthia; Steins, Anne; Kocher, Hemant M.; Medema, Jan P.; van Laarhoven, Hanneke W.; Bijlsma, Maarten F.

    2017-01-01

    Pancreatic ductal adenocarcinoma (PDAC) is marked by an abundant stromal deposition. This stroma is suspected to harbor both tumor-promoting and tumor-suppressing properties. This is underscored by the disappointing results of stroma targeting in clinical studies. Given the complexity of

  11. Anti-tumor activities of direct current (DC) therapy combined with fractionated radiation or chemotherapy

    International Nuclear Information System (INIS)

    Nakayama, Toshitake; Ito, Hisao; Hashimoto, Shozo

    1988-01-01

    Anti-tumor activities of direct current (DC) therapy combined with fractionated radiation or cyclophosphamide were studied in mice which were transplanted with murine fibrosarcoma (FSa) in the right thighs. Using TCD 50 assay, DC therapy, given in a single fraction, enhanced the effect of a single dose of radiation with the dose-modifying factor of 1.3. Tumor control rates were more improved by the combination therapy with the smaller doses of radiation than the larger ones. When DC therapy was applied one time immediately after the first radiation of fractionated ones, the combination therapy still showed the enhanced effect. However, both of DC therapy and radiation were divided in three fractions and DC therapy was applied everytime after radiation, tumor growth retardation were not different between the combination therapy and radiation alone. This result suggests that there is a minimum amount of Coulombs to improve the effect of radiation alone. On the other hand, DC therapy combined with cyclophosphamide given in one fraction showed the same enhancement effect as those divided in three fractions. These results suggest that DC therapy combined with radiation or cyclophosphamide is effective to improve tumor control, but the mechanisms to enhance the effect of radiation or cyclophosphamide are different. (author)

  12. Current advances in mathematical modeling of anti-cancer drug penetration into tumor tissues.

    Science.gov (United States)

    Kim, Munju; Gillies, Robert J; Rejniak, Katarzyna A

    2013-11-18

    Delivery of anti-cancer drugs to tumor tissues, including their interstitial transport and cellular uptake, is a complex process involving various biochemical, mechanical, and biophysical factors. Mathematical modeling provides a means through which to understand this complexity better, as well as to examine interactions between contributing components in a systematic way via computational simulations and quantitative analyses. In this review, we present the current state of mathematical modeling approaches that address phenomena related to drug delivery. We describe how various types of models were used to predict spatio-temporal distributions of drugs within the tumor tissue, to simulate different ways to overcome barriers to drug transport, or to optimize treatment schedules. Finally, we discuss how integration of mathematical modeling with experimental or clinical data can provide better tools to understand the drug delivery process, in particular to examine the specific tissue- or compound-related factors that limit drug penetration through tumors. Such tools will be important in designing new chemotherapy targets and optimal treatment strategies, as well as in developing non-invasive diagnosis to monitor treatment response and detect tumor recurrence.

  13. Treatment patterns, prescribing decision drivers, and predictors of complete response following disease recurrence in gastrointestinal stromal tumor patients-a chart extract-based approach.

    Science.gov (United States)

    Conley, Anthony Paul; Guerin, Annie; Sasane, Medha; Gauthier, Genevieve; Schwiep, Frances; Keir, Christopher Hunt; Wu, Eric Q

    2014-12-01

    The aim of this study was to investigate tumor characteristics, treatment patterns, and outcomes in recurrent KIT + GIST patients treated in a community practice setting. An online tool was used to retrieve data on 410 patients treated with adjuvant imatinib mesylate (IM) for primary resectable KIT + GIST, who discontinued, had a recurrence, and then restarted IM or initiated sunitinib. Tumor characteristics at recurrence, treatment patterns, and factors associated with post-recurrence complete response (CR) achievement were analyzed. About 72.7 % of patients did not have surgery post-recurrence as majority of them had unresectable (45 %), metastatic (40 %), or multifocal tumors (62.4 %). Following recurrence, 76.6 % of patients were re-started on IM and 23.4 % on sunitinib; patients were 7.37 times more likely to re-start IM if initial treatment duration was ≤18 months (p 12 months post-discontinuation, or they had a recurrence inside the GI system, lower or unknown Fletcher risk score at primary diagnosis, or lower mitotic rate, (odds ratio (OR) = 3.54, p < 0.001; OR = 2.64, p = 0.006; OR = 2.55, p = 0.007; and OR = 2.45, p = 0.002, respectively). About 22.4 % achieved CR; patients were more likely to achieve CR if they had unifocal tumor at recurrence, inside the GI system, of ≤2 cm, or had lower mitotic rate (OR = 2.61, p < 0.001; OR = 2.27, p = 0.036; OR = 2.16, p = 0.023, OR = 1.87, p = 0.017, respectively). IM treatment duration at primary diagnosis, time to develop recurrence after IM discontinuation, tumor location, and mitotic rate at recurrence were the main prescribing decision drivers. Tumor characteristics were the most important factor in achieving CR following c-KIT inhibitor retreatment.

  14. Alternating current electrical stimulation enhanced chemotherapy: a novel strategy to bypass multidrug resistance in tumor cells

    International Nuclear Information System (INIS)

    Janigro, Damir; Perju, Catalin; Fazio, Vincent; Hallene, Kerri; Dini, Gabriele; Agarwal, Mukesh K; Cucullo, Luca

    2006-01-01

    Tumor burden can be pharmacologically controlled by inhibiting cell division and by direct, specific toxicity to the cancerous tissue. Unfortunately, tumors often develop intrinsic pharmacoresistance mediated by specialized drug extrusion mechanisms such as P-glycoprotein. As a consequence, malignant cells may become insensitive to various anti-cancer drugs. Recent studies have shown that low intensity very low frequency electrical stimulation by alternating current (AC) reduces the proliferation of different tumor cell lines by a mechanism affecting potassium channels while at intermediate frequencies interfere with cytoskeletal mechanisms of cell division. The aim of the present study is to test the hypothesis that permeability of several MDR1 over-expressing tumor cell lines to the chemotherapic agent doxorubicin is enhanced by low frequency, low intensity AC stimulation. We grew human and rodent cells (C6, HT-1080, H-1299, SKOV-3 and PC-3) which over-expressed MDR1 in 24-well Petri dishes equipped with an array of stainless steel electrodes connected to a computer via a programmable I/O board. We used a dedicated program to generate and monitor the electrical stimulation protocol. Parallel cultures were exposed for 3 hours to increasing concentrations (1, 2, 4, and 8 μM) of doxorubicin following stimulation to 50 Hz AC (7.5 μA) or MDR1 inhibitor XR9576. Cell viability was assessed by determination of adenylate kinase (AK) release. The relationship between MDR1 expression and the intracellular accumulation of doxorubicin as well as the cellular distribution of MDR1 was investigated by computerized image analysis immunohistochemistry and Western blot techniques. By the use of a variety of tumor cell lines, we show that low frequency, low intensity AC stimulation enhances chemotherapeutic efficacy. This effect was due to an altered expression of intrinsic cellular drug resistance mechanisms. Immunohistochemical, Western blot and fluorescence analysis revealed

  15. Endometrial Stromal Sarcoma: A Rare Entity

    International Nuclear Information System (INIS)

    Jabeen, S.; Anwar, S.; Fatima, N.

    2015-01-01

    Endometrial Stromal Sarcoma (ESS) is a hormone sensitive tumor. It is a rare gynecological tumor and is considered to occur more often in pre-menopausal women. A proper pre-operative diagnosis is difficult and confirmed in most cases after hysterectomy for a presumed benign disease. Endometrial sampling, ultrasound, and magnetic resonance imaging can provide diagnostic clues. For early disease complete surgical cure is possible, however, adjuvant therapy is available for recurrence. This case of Low Grade Endometrial Stromal Sarcoma (LGESS) in a 21 years old woman was presented as irregular vaginal bleeding. Clinical diagnosis of fibroid was made but analysis of endometrium showed ESS confirmed on hysterectomy specimen. One should consider it in any case with rapid fibroid enlargement. (author)

  16. A long-term follow-up of the imatinib mesylate treatment for the patients with recurrent gastrointestinal stromal tumor (GIST): the liver metastasis and the outcome

    International Nuclear Information System (INIS)

    Zhu, Jiang; Yang, Yu; Zhou, Lin; Jiang, Ming; Hou, Mei

    2010-01-01

    About 80% of patients with GIST would experience tumor recurrence or metastasis after radical resection. The most common site of the metastasis is the liver. Imatinib mesylate has been proved effective for advanced GIST. The present study was designed to further observe the effectiveness of the imatinib mesylate treatment on the recurrent GIST and the correlation between the liver metastasis and the outcome. Forty-two patients who had recurrent GIST after the first radical resection were enrolled. According to the recurrent sites, the patients were divided into 3 groups: group LG (recurrent liver GISTs), group AG (recurrent abdominal GISTs) and group ALG (recurrent abdominal and liver GISTs). All the patients were given imatinib mesylate at an initial dose of 400 mg per day. Their clinical data was prospectively collected. A follow-up over 3 years was conducted. Tumor response, time to progression and survival were evaluated. The long-term Imatinib mesylate treatment was safe and well tolerated. At a median follow-up time for 39.5 months, the 3-year survival rate was 66.7%. Median TTP and OS were 37 months (95% CI: 28.2~45.8 months) and 48 months (95% CI: 37.0~58.9 months), respectively. There was no statistical difference in tumor response among the 3 groups. The similar TTP (P = 0.291) and OS (P = 0.160) were observed in the 3 groups. The imatinib mesylate treatment could prolong the survival of the patients who have recurrent GIST after the radical surgery in spite of an existence of the liver metastasis. Survival was not significantly affected by liver metastasis when imatinib mesylate was warranted

  17. TPL2 (Therapeutic Targeting Tumor Progression Locus-2)/ATF4 (Activating Transcription Factor-4)/SDF1α (Chemokine Stromal Cell-Derived Factor-α) Axis Suppresses Diabetic Retinopathy.

    Science.gov (United States)

    Lai, De-Wei; Lin, Keng-Hung; Sheu, Wayne Huey-Herng; Lee, Maw-Rong; Chen, Chung-Yu; Lee, Wen-Jane; Hung, Yi-Wen; Shen, Chin-Chang; Chung, Tsung-Ju; Liu, Shing-Hwa; Sheu, Meei-Ling

    2017-09-01

    Diabetic retinopathy is characterized by vasopermeability, vascular leakage, inflammation, blood-retinal barrier breakdown, capillary degeneration, and neovascularization. However, the mechanisms underlying the association between diabetes mellitus and progression retinopathy remain unclear. TPL2 (tumor progression locus 2), a serine-threonine protein kinase, exerts a pathological effect on vascular angiogenesis. This study investigated the role of N ε -(carboxymethyl)lysine, a major advanced glycation end products, and the involved TPL2-related molecular signals in diabetic retinopathy using models of in vitro and in vivo and human samples. Serum N ε -(carboxymethyl)lysine levels and TPL2 kinase activity were significantly increased in clinical patients and experimental animals with diabetic retinopathy. Intravitreal administration of pharmacological blocker or neutralizing antibody inhibited TPL2 and effectively suppressed the pathological characteristics of retinopathy in streptozotocin-induced diabetic animal models. Intravitreal VEGF (vascular endothelial growth factor) neutralization also suppressed the diabetic retinopathy in diabetic animal models. Mechanistic studies in primary human umbilical vein endothelial cells and primary retinal microvascular endothelial cells from streptozotocin-diabetic rats, db/db mice, and samples from patients with diabetic retinopathy revealed a positive parallel correlation between N ε -(carboxymethyl)lysine and the TPL2/chemokine SDF1α (stromal cell-derived factor-α) axis that is dependent on endoplasmic reticulum stress-related molecules, especially ATF4 (activating transcription factor-4). This study demonstrates that inhibiting the N ε -(carboxymethyl)lysine-induced TPL2/ATF4/SDF1α axis can effectively prevent diabetes mellitus-mediated retinal microvascular dysfunction. This signaling axis may include the therapeutic potential for other diseases involving pathological neovascularization or macular edema. © 2017

  18. Guidelines for time-to-event end point definitions in sarcomas and gastrointestinal stromal tumors (GIST) trials: results of the DATECAN initiative (Definition for the Assessment of Time-to-event Endpoints in CANcer trials)†.

    Science.gov (United States)

    Bellera, C A; Penel, N; Ouali, M; Bonvalot, S; Casali, P G; Nielsen, O S; Delannes, M; Litière, S; Bonnetain, F; Dabakuyo, T S; Benjamin, R S; Blay, J-Y; Bui, B N; Collin, F; Delaney, T F; Duffaud, F; Filleron, T; Fiore, M; Gelderblom, H; George, S; Grimer, R; Grosclaude, P; Gronchi, A; Haas, R; Hohenberger, P; Issels, R; Italiano, A; Jooste, V; Krarup-Hansen, A; Le Péchoux, C; Mussi, C; Oberlin, O; Patel, S; Piperno-Neumann, S; Raut, C; Ray-Coquard, I; Rutkowski, P; Schuetze, S; Sleijfer, S; Stoeckle, E; Van Glabbeke, M; Woll, P; Gourgou-Bourgade, S; Mathoulin-Pélissier, S

    2015-05-01

    The use of potential surrogate end points for overall survival, such as disease-free survival (DFS) or time-to-treatment failure (TTF) is increasingly common in randomized controlled trials (RCTs) in cancer. However, the definition of time-to-event (TTE) end points is rarely precise and lacks uniformity across trials. End point definition can impact trial results by affecting estimation of treatment effect and statistical power. The DATECAN initiative (Definition for the Assessment of Time-to-event End points in CANcer trials) aims to provide recommendations for definitions of TTE end points. We report guidelines for RCT in sarcomas and gastrointestinal stromal tumors (GIST). We first carried out a literature review to identify TTE end points (primary or secondary) reported in publications of RCT. An international multidisciplinary panel of experts proposed recommendations for the definitions of these end points. Recommendations were developed through a validated consensus method formalizing the degree of agreement among experts. Recommended guidelines for the definition of TTE end points commonly used in RCT for sarcomas and GIST are provided for adjuvant and metastatic settings, including DFS, TTF, time to progression and others. Use of standardized definitions should facilitate comparison of trials' results, and improve the quality of trial design and reporting. These guidelines could be of particular interest to research scientists involved in the design, conduct, reporting or assessment of RCT such as investigators, statisticians, reviewers, editors or regulatory authorities. © The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  19. Is 3-years duration of adjuvant imatinib mesylate treatment sufficient for patients with high-risk gastrointestinal stromal tumor? A study based on long-term follow-up.

    Science.gov (United States)

    Lin, Jian-Xian; Chen, Qing-Feng; Zheng, Chao-Hui; Li, Ping; Xie, Jian-Wei; Wang, Jia-Bin; Lu, Jun; Chen, Qi-Yue; Cao, Long-Long; Lin, Mi; Tu, Ru-Hong; Huang, Chang-Ming

    2017-04-01

    The therapy for gastrointestinal stromal tumors (GIST) has changed significantly since the use of imatinib mesylate (IM). However, the appropriate duration of receiving adjuvant IM for patients with high-risk GIST who underwent R0 resection is still controversial. From January 2005 to December 2014, 234 patients who underwent R0 resection and were treated with adjuvant imatinib at our institution were identified from a prospectively collected database. The effect of the medication duration on the long-term outcomes was analyzed. In this study, 140 cases were male and 94 cases were female, and the mean age was 57.5 ± 11.4 years. The most common site was the stomach (103 cases, 44%), followed by the small intestine (81 cases, 34.6%). The 5 year recurrence-free survival (RFS) rate and overall survival (OS) rate in the whole groups were 76.2 and 83.4%, respectively. The patient's prognosis was improved due to the prolongation of the time of receiving the imatinib treatment (P  0.05). However, in the high-risk patients, the RFS rates of the 1-year group, 1-3-years group, 3-5-years group and more than 5 years group were 36.5, 68.7, 71.2 and 90.8%, respectively, and the OS rates were 36.7, 76.6, 84.0 and 97.4%, respectively (P imatinib treatment for at least 5 years.

  20. All-trans retinoic acid inhibits KIT activity and induces apoptosis in gastrointestinal stromal tumor GIST-T1 cell line by affecting on the expression of survivin and Bax protein

    Directory of Open Access Journals (Sweden)

    Taguchi Takahiro

    2010-12-01

    Full Text Available Abstract Background Imatinib, a selective tyrosine kinase inhibitor, has been used as a standard first-line therapy for irresectable and metastasized gastrointestinal stromal tumor (GIST patients. Unfortunately, most patients responding to imatinib will eventually exhibit imatinib-resistance, the cause of which is not fully understood. The serious clinical problem of imatinib-resistance demands alternative therapeutic strategy. This study was conducted to investigate the effect of all-trans retinoic acid (ATRA on GIST cell lines. Methods Cell proliferation was determined by trypan blue dye exclusion test. Western blot analysis was performed to test the expression of activated KIT, its downstream proteins, and apoptosis associated proteins. The cytotoxic interactions of imatinib with ATRA were evaluated using the isobologram of Steel and Peckham. Results and conclusion In this work, for the first time we have demonstrated that ATRA affected on cell proliferation of GIST-T1 and GIST-882 cell line through inhibition of cell growth in a dose dependent manner and induced apoptosis. High dose of ATRA induced morphologic change in GIST-T1 cells, rounded-up cells, and activated the caspase-3 protein. In further examination, we found that the ATRA-induced apoptosis in GIST-T1 cells was accompanied by the down-regulated expression of survivin and up-regulated expression of Bax protein. Moreover, ATRA suppressed the activity of KIT protein in GIST-T1 cells and its downstream signal, AKT activity, but not MAPK activity. We also have demonstrated that combination of ATRA with imatinib showed additive effect by isobologram, suggesting that the combination of ATRA and imatinib may be a novel potential therapeutic option for GIST treatment. Furthermore, the scracht assay result suggested that ATRA was a potential reagent to prevent the invasion or metastasis of GIST cells.

  1. Current trends in surgical approach and outcomes following pituitary tumor resection.

    Science.gov (United States)

    Villwock, Jennifer A; Villwock, Mark R; Goyal, Parul; Deshaies, Eric M

    2015-06-01

    The goals of pituitary tumor resection include normalizing endocrine function, relieving mass effect, and minimizing risk of recurrence. This study investigated current trends in costs and complications for transfrontal and transsphenoidal pituitary surgery. Retrospective review of the 2008-2011 Nationwide Inpatient Sample for patients undergoing pituitary lesion resection. Demographics and outcomes were compared between transfrontal and transsphenoidal surgical approaches using χ(2) tests. Multivariate analysis was performed to investigate outcomes while controlling for confounders. There were 8,543 admissions for resection of pituitary lesions that met our inclusion criteria. Most (>90%) were treated transsphenoidally. The transfrontal approach was most frequent in the young (<35 years) and in the South. Rates of mortality and complications were higher in patients undergoing transfrontal surgery. Multivariate analysis found transsphenoidal resection was associated with a reduction in hospital costs and length of stay by over 50%; low-volume hospitals had increased cost and length of stay. There was an increased rate of transfrontal approaches at low-volume centers. Multiple factors influence outcomes of pituitary tumor resection. Transsphenoidal pituitary surgery is associated with a shorter length of stay, lower cost, and lower complication rates when compared to transfrontal surgery. Case specifics, including tumor location and size, influence approach and lead to a selection bias that cannot be controlled for in the present study. The prevalence of transfrontal resections at low-volume centers may indicate an area of further investigation. Additionally, when controlling for surgical approach, low-volume centers were found to adversely affect economic outcomes and also warrants investigation. 2c. © 2015 The American Laryngological, Rhinological and Otological Society, Inc.

  2. The expression of succinate dehydrogenase in breast phyllodes tumor.

    Science.gov (United States)

    Choi, Junjeong; Kim, Do Hee; Jung, WooHee; Koo, Ja Seung

    2014-10-01

    The purpose of this study is to investigate the expression of succinate dehydrogenase (SDH)A, SDHB, and HIF-1α in phyllodes tumors and the association with clinic-pathologic factors. Using tissue microarray (TMA) for 206 phyllodes tumor cases, we performed immunohistochemical stains for SDHA, SDHB, and HIF-1α and analyzed their expression in regard to clinicopathologic parameters of each case. The cases were comprised of 156 benign, 34 borderline, and 16 malignant phyllodes tumors. The expression of stromal SDHA and epithelial- and stromal- SDHB increased as the tumor progressed from benign to malignant (P⟨0.001). There were five stromal SDHA-negative cases and 31 stromal SDHB-negative cases. SDHB negativity was associated with a lower histologic grade (P=0.054) and lower stromal atypia (P=0.048). Univariate analysis revealed that a shorter disease free survival (DFS) was associated with stromal SDHB high-positivity (P=0.013) and a shorter overall survival (OS) was associated with high-positivity of stromal SDHA and SDHB (P⟨0.001 and P⟨0.001, respectively). The multivariate Cox analysis with the variables stromal cellularity, stromal atypia, stromal mitosis, stromal overgrowth, tumor margin, stromal SDHA expression, and stromal SDHB expression revealed that stromal overgrowth was associated with a shorter DFS (hazard ratio: 24.78, 95% CI: 3.126-196.5, P=0.002) and a shorter OS (hazard ratio: 176.7, 95% CI: 8.466-3691, P=0.001). In conclusion, Tumor grade is positively correlated with SDHA and SDHB expression in the tumor stroma in phyllodes tumors of the breast. This result may be attributed to the increased metabolic demand in high grade tumors.

  3. Current diagnosis of tumors developed in the internal auditory canal and cerebellopontine angle

    International Nuclear Information System (INIS)

    Vignaud, J.; Doyon, D.

    1988-01-01

    The introduction of CT scan and, more recently, magnetic resonance imaging, has radically changed the diagnostic approach to tumors developed in the internal auditory canal and cerebellopontine angle. CT scan with intravenous injection visualizes tumors lying in the cerebellopontine angle. Magnetic resonance imaging, especially using gadolinium, is a very accurate means for diagnosing tumors of both the auditory canal and cerebellopontine angle [fr

  4. Current Status and Perspectives on Tumor Markers in Cancers of Digestive Organs (Clinical Usefulness of Tumor Markers)

    OpenAIRE

    藍沢, 喜久雄; 畠山, 勝義; 酒井, 靖夫; 白井, 良夫; 塚田, 一博; 田中, 乙雄; Aizawa, Kikuo; Hatakeyama, Katsuyoshi; Sakai, Yasuo; Shirai, Yoshio; Tsukada, Kazuhiro; Tanaka, Otsuo

    1994-01-01

    Carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) have been routinely utilized in diagnosis and monitoring of patients with cancers of digestive organ (esophagus, stomach, gallbladder, biliary duct, pancreas, colon and rectum) in our division. They are clinically useful for diagnosis and evaluation of the clinical stage, status of lymph node and hematogenous metastasis, resectability, and detection of tumor reccurence in advanced cancer, however, there are no diagnostic va...

  5. Fibroadenoma With Pleomorphic Stromal Giant Cells: It's Not as Bad as It Looks!

    Science.gov (United States)

    Wawire, Jonathan; Singh, Kamaljeet; Steinhoff, Margaret M

    2017-08-01

    Clinically relevant histological categorization of fibroepithelial lesions can be a daunting task, especially in a core needle biopsy. Assessment of stromal nuclear atypia, including nuclear pleomorphism and mitotic activity, is a key morphological feature employed to classify fibroepithelial lesions. We describe a case of fibroadenoma with markedly atypical nuclear features in the stromal cells that led to misclassification as phyllodes tumor in the core needle biopsy. Excision showed a fibroadenoma containing pleomorphic stromal giant cells, with occasional mitotic figures, including atypical forms. Aforementioned nuclear findings in a fibroepithelial lesion raise a legitimate question of phyllodes tumor. Knowledge of this pitfall may help avoid overtreatment of an otherwise benign fibroepithelial lesion.

  6. Equine corneal stromal abscesses

    DEFF Research Database (Denmark)

    Henriksen, M. D. L.; Andersen, P. H.; Plummer, C. E.

    2013-01-01

    The last 30 years have seen many changes in the understanding of the pathogenesis and treatment of equine corneal stromal abscesses (SAs). Stromal abscesses were previously considered an eye problem related to corneal bacterial infection, equine recurrent uveitis, corneal microtrauma and corneal...... foreign bodies in horses. They were more commonly diagnosed in horses living in subtropical climatic areas of the world. Therapeutic recommendations to treat equine SAs were historically nearly always a medical approach directed at bacteria and the often associated severe iridocyclitis. Today...... the pathogenesis of most equine SAs appears to be more often related to fungal inoculation of the anterior corneal stroma followed by posterior migration of the fungi deeper into the corneal stroma. There is also now an increased incidence of diagnosis of corneal SAs in horses living in more temperate climates...

  7. Skeletal (stromal) stem cells

    DEFF Research Database (Denmark)

    Abdallah, Basem M; Kermani, Abbas Jafari; Zaher, Walid

    2015-01-01

    Skeletal (marrow stromal) stem cells (BMSCs) are a group of multipotent cells that reside in the bone marrow stroma and can differentiate into osteoblasts, chondrocytes and adipocytes. Studying signaling pathways that regulate BMSC differentiation into osteoblastic cells is a strategy....../preadipocyte factor 1 (Dlk1/Pref-1), the Wnt co-receptor Lrp5 and intracellular kinases. This article is part of a Special Issue entitled: Stem Cells and Bone....

  8. Genetics Home Reference: gastrointestinal stromal tumor

    Science.gov (United States)

    ... Corless CL, Duensing A, McGreevey L, Chen CJ, Joseph N, Singer S, Griffith DJ, Haley A, Town A, ... National Institutes of Health National Library of Medicine Lister Hill National Center for Biomedical Communications 8600 Rockville ...

  9. Influence of Ionizing Radiation on Stromal-Epithelial Intercellular Communication in Esophageal Carcinogenesis

    Science.gov (United States)

    Patel, Zarana S.; Kalabis, Jiri; Rustgi, Anil K.; Cucinotta, Francis A.; Huff, Janice L.

    2010-01-01

    Esophageal cancer is the 6th leading cause of cancer death worldwide. Its development is associated with a variety of risk factors including tobacco use, heavy alcohol consumption, human papilloma virus infection, and certain dietary factors such as trace mineral and vitamin deficiencies. An association with ionizing radiation exposure is revealed by the high excess relative risk for squamous cell carcinoma of the esophagus observed in the survivors of the atomic bomb detonations in Japan. It is also seen as a secondary malignancy in patients who received radiotherapy for breast and thoracic cancers; additionally, patients with head/neck and oral squamous cell cancers are at increased risk for metachronous esophageal squamous cell cancers. This malignancy is rapidly fatal, mainly because it remains asymptomatic until late, advanced stages when the disease is rarely curable. The stromal microenvironment plays an essential role in the maintenance and modulation of normal epithelial cell growth and differentiation and cross talk between the epithelial and stromal compartments can influence many aspects of malignant progression, including tumor cell proliferation, migration, invasion and recruitment of new blood vessels. To test the hypothesis that radiation exposure plays a role in esophageal carcinogenesis via non-targeted mechanisms involving stromal-epithelial cell communication, we are studying radiation effects on hTERT-immortalized human esophageal epithelial cells and genetic variants grown in co-culture with human esophageal stromal fibroblasts (Okawa et al., Genes & Dev. 2007. 21: 2788-2803). We examined how radiation treatment of stromal fibroblasts affected epithelial migration and invasion, behaviors associated with cancer promotion and progression. Chemotactic and haptotactic migration of epithelial cells stimulated by conditioned media from irradiated fibroblasts was measured using assays conducted in Transwell cell culture chambers. Our results using

  10. Radiotherapy for pediatric brain tumors: Standards of care, current clinical trials, and new directions

    International Nuclear Information System (INIS)

    Goldwein, Joel W.

    1995-01-01

    The objectives of the course are to evaluate the role of radiation therapy in the treatment of pediatric brain tumors. Areas where the role is evolving will be identified, and the results of clinical trials which been mounted to clarify radiotherapy's role will be reviewed. Brain tumors are the second most common malignancy of childhood after leukemias and lymphomas. However, they remain the most common group of childhood tumors to require radiation therapy. Therefore, a thorough understanding of these tumors, and the appropriate role of surgery, radiation and chemotherapy is critical. Issues surrounding the management of sequelae are no less important. The role of radiotherapy for the treatment of these tumors is far different from that for adults. These differences relate to the profound potential for sequelae from therapy, the higher overall cure rates, and the utility of multimodality therapies. In addition, the rarity of childhood brain tumors compared with adults' makes them more difficult to study. In this session, the following issues will be reviewed; 1. Incidence of pediatric brain tumors, 2. General issues regarding symptoms, diagnosis, diagnostic tests and evaluation, 3. Importance of a team approach, 4. General issues regarding treatment sequelae, 5. Specific tumor types/entities; a. Cerebellar Astrocytomas b. Benign and malignant Gliomas including brainstem and chiasmatic lesions c. Primitive Neuroectodermal Tumors (PNET) and Medulloblastoma d. Ependymomas e. Craniopharyngiomas f. Germ cell tumors g. Miscellaneous and rare pediatric brain tumors 6. Management of sequelae 7. New and future directions a. Treatment of infants b. The expanding role of chemotherapy c. Advances in radiotherapy. The attendees will complete the course with a better understanding of the role that radiation therapy plays in the treatment of pediatric brain tumors. They will be knowledgeable in the foundation for that role, and the changes which are likely to take place in the

  11. Involvement of Bmi-1 gene in the development of gastrointestinal stromal tumor by regulating p16Ink4A/p14ARF gene expressions: An in vivo and in vitro study.

    Science.gov (United States)

    Wang, Jiang-Li; Wu, Jiang-Hong; Hong, Cai; Wang, Ya-Nong; Zhou, Ye; Long, Zi-Wen; Zhou, Ying; Qin, Hai-Shu

    2017-12-01

    This study was conducted in order to explore the role that Bmi-1 plays during the development of a gastrointestinal stromal tumor (GIST) by regulation of the p16 Ink4A and p14 ARF expressions. Eighty-six patients diagnosed with GIST were selected to take part in this experiment. The Bmi-1 protein expressions in GIST and adjacent normal tissues were detected using immunohistochemistry and further analyzed by using photodensitometry. To monitor and track the progression of the GIST, a 3-year follow-up was conducted for all affected patients. After cell transfection, the GIST cells were assigned into the control group (without transfection), the negative control (NC) group (transfected with Bmi-1-Scramble plasmid), and the Bmi-1 shRNA group (transfected with the pcDNA3.1-Bmi-1 shRNA plasmid). Protein and mRNA expressions collected from Bmi-1, p16 lnk4A , P14 ARF , cyclin D1, and CDK4 were measured using both the RT-qPCR and western blotting methods Cell senescence was assessed and obtained by using the β-Galactosidase (β-Gal) activity assay. The use of a Soft agar colony formation assay and CCK-8 assay were performed in order to detect the cell growth and subsequent proliferation. Cell invasion and migration were analyzed using the Transwell assay and scratch test. Bmi-1 in the GIST tissues was found to be significantly higher and the p16 lnk4A and P14 ARF expressions were lower than those in the adjacent normal tissues. Bmi-1 was negatively correlated with p16 lnk4A and P14 ARF expressions according to the correlation analysis. Bmi-1 expression was associated with the TNM stage, postoperative recurrence, metastasis, tumor size, and the 5-year survival rate. Area under ROC curve was calculated at 0.884, and sensitivity, specificity, and accuracy of Bmi-1 predicting the GIST were 67.44%, 97.67%, and 65.12%, respectively. Patients exhibiting a high Bmi-1 expression in the GIST tissues had lower survival rates than those with low Bmi-1 expression. In comparison with

  12. Mammary fibroadenoma with pleomorphic stromal cells.

    Science.gov (United States)

    Abid, Najla; Kallel, Rim; Ellouze, Sameh; Mellouli, Manel; Gouiaa, Naourez; Mnif, Héla; Boudawara, Tahia

    2015-01-01

    The presence of enlarged and pleomorphic nuclei is usually regarded as a feature of malignancy, but it may on occasion be seen in benign lesions such as mammary fibroadenomas. We present such a case of fibroadenoma occurring in a 37-year-old woman presenting with a self-palpable right breast mass. Histological examination of the tumor revealed the presence of multi and mononucleated giant cells with pleomorphic nuclei. The recognition of the benign nature of these cells is necessary for differential diagnosis from malignant lesions of the breast. fibroadenoma - pleomorphic stromal cells - atypia - breast.

  13. Extragenital endometrial stromal sarcoma arising in endometriosis.

    Science.gov (United States)

    Alcázar, Juan Luis; Guerriero, Stefano; Ajossa, Silvia; Parodo, Giuseppina; Piras, Bruno; Peiretti, Michele; Jurado, Matías; Idoate, Miguel Ángel

    2012-01-01

    The diagnosis rate of deep pelvic endometriosis is increasing. Endometrial stromal sarcoma (ESS) is a rare neoplasm. Extragenital ESS is an extremely uncommon event. Very few cases of extragenital ESS have been reported to date. The diagnosis of this entity is very difficult in some instances. Knowledge about its management is also limited. In this paper, we review the current literature on the clinical management, histology, immunohistochemistry, treatment and outcome of ESS arising in pelvic endometriosis. Copyright © 2012 S. Karger AG, Basel.

  14. Robot-assisted minimally invasive surgery for pediatric solid tumors: a systematic review of feasibility and current status.

    Science.gov (United States)

    Cundy, Thomas P; Marcus, Hani J; Clark, James; Hughes-Hallett, Archie; Mayer, Erik K; Najmaldin, Azad S; Yang, Guang-Zhong; Darzi, Ara

    2014-04-01

    Open surgery remains the primary technique for resection of pediatric solid tumors despite the popularity of minimally invasive surgery (MIS) for oncological indications in adults and nononcological indications in children. Robot-assisted surgery offers technical and ergonomic advantages that might make MIS more achievable in this setting, permitting benefits for both the patient and surgeon. The aim of this study is to critically appraise the current status of robot-assisted MIS for pediatric solid tumors. A systematic search of multiple electronic literature databases was undertaken, supplemented by several relevant secondary sources. A total of 23 publications met eligibility criteria, reporting 40 cases overall. Indications for surgery were widely varied, with over 20 different pathologies described. One-third of tumors were classified as malignant. Most procedures involved abdominal or retroperitoneal located tumors in adolescent patients (age range, 1-18 years). The collective complication and conversion rates were 10% and 12.5%, respectively. Oncological adverse events involved two isolated events of tumor spillage and residual disease. The evidence is limited to case reports and small case series only. For the diverse and highly selective cases in this review, robot-assisted MIS seems safe and feasible. Current status is low volume, in a relatively static state of adoption, and without any apparent index pathology or procedure. The benefits of robot assistance seem well suited but remain unsubstantiated by evidence. Higher quality studies are needed to determine true safety and efficacy. Georg Thieme Verlag KG Stuttgart · New York.

  15. Need for Lacrimal Bypass Surgery after Medial Canthal Tumor Resection: Survey of Current Practices

    Directory of Open Access Journals (Sweden)

    Christopher J. Calvano

    2013-02-01

    Conclusions: SebC and M follow-up intervals trend shorter, while most respondents follow these tumors post-excision > 5 years. > 25% of surgeons follow all tumors for > 60 months. CDCR is delayed for > 12 months by > 75% of surgeons for all tumors. 8% perform CDCR at the time of excision, and 14% reported local/orbital recurrence following CDCR with 52% obtaining pre-CDCR imaging. These results support extended follow-up before CDCR combined with appropriate imaging/testing to minimize morbidity/mortality. [Arch Clin Exp Surg 2013; 2(1.000: 1-7

  16. Transition of endometrial stromal sarcoma into high-grade sarcoma.

    Science.gov (United States)

    Amant, Frederic; Woestenborghs, Heidi; Vandenbroucke, Vanessa; Berteloot, Patrick; Neven, Patrick; Moerman, Philippe; Vergote, Ignace

    2006-12-01

    Endometrial stromal sarcoma typically is of low grade and hormone-sensitive. Although these characteristics result in an indolent behavior, little data are available on the evolution over time. We report on two cases where microscopic and immunohistochemic assessment of the tumor on several occasions during 8 and 25 years of follow up enabled us to document a transition of a low-grade into a high-grade malignancy. These were mainly characterized by increased cellular atypia, absence of spiral arterioles and an increased mitotic index and proliferation index (MIB1). Since this transition was related to clinical loss of hormone sensitivity, the therapeutic approach consisting of hormonal treatment in combination with repetitive surgery was switched to chemotherapy only. These long-term follow up data provide insight in endometrial stromal sarcoma tumor biology and highlight the importance of sampling recurrent tumors to estimate biologic behavior in order to tailor subsequent treatment.

  17. Giant cell tumor of bone: current review of morphological, clinical, radiological, and therapeutic characteristics

    Directory of Open Access Journals (Sweden)

    Georgi P. Georgiev

    2014-09-01

    Full Text Available Giant cell tumor of bone accounts for about 5% of all primary bone tumors in adults and is still one of the most obscure and intensively examined tumors of bone. This largely results from the lack of uniform clinical, radiographic, histological or morphological aspects that allow prediction of recurrence. Classified by the World Health Organization as “an aggressive, potentially malignant lesion”, the giant cell tumor of bone could give lung metastases, could undergo malignant degeneration or could have multicentric localization. It usually develops in long bones but can also occur in unusual locations. The common presenting symptom is increasing pain at the tumor site. Standard treatment ranges from curettage to wide resection, with reports of varying oncological and functional results. The recurrence rate is high during the first 2-3 years after surgery regardless of pre-operative tumor stage. Herein, we discuss the morphological, clinical, radiological, and therapeutic characteristics of this pathologic entity as well as its differential diagnosis. J Clin Exp Invest 2014; 5 (3: 475-485

  18. Mesenchymal stromal cells: misconceptions and evolving concepts.

    Science.gov (United States)

    Phinney, Donald G; Sensebé, Luc

    2013-02-01

    Nearly half a century has passed since the publication of the first articles describing plastic-adherent cells from bone marrow, referred to initially as colony-forming unit fibroblasts, then marrow stromal cells, mesenchymal stem cells and most recently multipotent mesenchymal stromal cells (MSCs). As expected, our understanding of the nature and biologic functions of MSCs has undergone major paradigm shifts over this time. Despite significant advances made in deciphering their complex biology and therapeutic potential in both experimental animal models and human clinical trials, numerous misconceptions regarding the nature and function of MSCs have persisted in the field. Continued propagation of these misconceptions in some cases may significantly impede the advancement of MSC-based therapies in clinical medicine. We have identified six prevalent misconceptions about MSCs that we believe affect the field, and we attempt to rectify them based on current available data. Copyright © 2013 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

  19. Uterine sarcoma - current perspectives.

    Science.gov (United States)

    Benson, Charlotte; Miah, Aisha B

    2017-01-01

    Uterine sarcomas comprise a group of rare tumors with differing tumor biology, natural history and response to treatment. Diagnosis is often made following surgery for presumed benign disease. Currently, preoperative imaging does not reliably distinguish between benign leiomyomas and other malignant pathology. Uterine leiomyosarcoma is the most common sarcoma, but other subtypes include endometrial stromal sarcoma (low grade and high grade), undifferentiated uterine sarcoma and adenosarcoma. Clinical trials have shown no definite survival benefit of adjuvant radiotherapy or chemotherapy and have been hampered by the rarity and heterogeneity of these disease types. There is a role of adjuvant treatment in carefully selected cases following multidisciplinary discussion at sarcoma reference centers. In patients with metastatic disease, systemic chemotherapy can then be considered. There is activity of a number of agents, including doxorubicin, trabectedin, gemcitabine-based chemotherapy, eribulin and pazopanib. Patients should be considered for clinical trial entry where possible. Close international collaboration is important to allow progress in this group of diseases.

  20. Influence of Ionizing Radiation on Stromal-Epithelial Communication in Esophageal Carcinogenesis

    Science.gov (United States)

    Huff, Janice; Patel, Zarana; Grugan, Katharine; Rustgi, Anil; Cucinotta, Francis A.

    Esophageal cancer is the 6th leading cause of cancer death worldwide and is associated with a variety of risk factors including tobacco use, heavy alcohol consumption, human papilloma virus infection, and certain dietary factors such as trace mineral and vitamin deficiencies. A connection with ionizing radiation exposure is revealed by the high excess relative risk for esophageal squamous cell carcinoma observed in the survivors of the atomic bomb detonations in Japan. Esophageal carcinomas are also seen as secondary malignancies in patients who received radiotherapy for breast and thoracic cancers; additionally, patients with head/neck and oral squamous cell cancers are at increased risk for metachronous esophageal squamous cell cancers. This malignancy is rapidly fatal, mainly because it remains asymptomatic until late, advanced stages when the disease is rarely responsive to treatment. In normal epithelium, the stromal microenvironment is essential for the maintenance and modulation of cell growth and differentiation. Cross talk between the epithelial and stromal compartments can influence many aspects of malignant progression, including tumor cell proliferation, migration, invasion and recruitment of new blood vessels. To test the hypothesis that radiation exposure plays a role in esophageal carcinogenesis via non-targeted mechanisms involving stromal-epithelial cell communication, we are studying radiation effects on hTERT-immortalized human esophageal epithelial cells and genetic variants grown in co-culture with human esophageal stromal fibrob-lasts (Okawa et al., Genes Dev. 2007. 21: 2788-2803). We examined how irradiation of stromal fibroblasts affected epithelial migration and invasion, behaviors associated with cancer promotion and progression. These assays were conducted in modified Boyden chambers using conditioned media from irradiated fibroblasts. Our results using low LET gamma radiation showed a dose-dependent increase in migration of epithelial

  1. Stromal-epithelial dynamics in response to fractionated radiotherapy

    Science.gov (United States)

    Qayyum, Muqeem Abdul

    Radiotherapy is central to the management of a number of human cancers, either as an adjuvant or primary treatment modality. The principal objective in irradiating tumors is to permanently inhibit their proliferative ability. More than half of all malignancies are primarily treated with radiation, but the heterotypic nature of tumor cells greatly complicates their response to radiotherapy. The need for reliable parameters to predict tumor and normal tissue response to radiation is therefore a prime concern of clinical oncology. Post-operative radiotherapy has commonly been used for early stage breast cancer to treat residual disease. There is continued debate as to what might be the proper dose per fraction as well as the total dose of radiation that needs to be prescribed to prevent disease recurrence. Countries outside the US have adopted increased dose fractionation (i.e., hypofractionation) schemes for early stage breast cancer as a standard of practice; however there is a lack of confidence in these approaches in the United States. The tumor microenvironment plays a significant role in regulating the progression of carcinomas, although the mechanisms are not entirely clear. The primary objective of this work was to characterize, through mechanobiological and radiobiological modeling, a test bed for radiotherapy fractionation techniques assessment. Our goal is to understand how the tumor microenvironment responds to dose fractionation schemes for Breast Conserving Therapy (BCT). Although carcinomas are the major concern for oncology, in this project, the goal is to understand how the stromal microenvironment influences behavior of the cancer cell populations. By classifying 3-D cellular co-cultures as having a reactive or quiescent stroma using the mechanobiology profile (culture stiffness,cellular activation, differentiation, and proliferation) we aim to differentiate the effectiveness of various fractionation schemes. The benefits of understanding heterotypic

  2. Potential Effect of CD271 on Human Mesenchymal Stromal Cell Proliferation and Differentiation

    Directory of Open Access Journals (Sweden)

    Giovanna Calabrese

    2015-07-01

    Full Text Available The Low-Affinity Nerve Growth Factor Receptor (LNGFR, also known as CD271, is a member of the tumor necrosis factor receptor superfamily. The CD271 cell surface marker defines a subset of multipotential mesenchymal stromal cells and may be used to isolate and enrich cells derived from bone marrow aspirate. In this study, we compare the proliferative and differentiation potentials of CD271+ and CD271− mesenchymal stromal cells. Mesenchymal stromal cells were isolated from bone marrow aspirate and adipose tissue by plastic adherence and positive selection. The proliferation and differentiation potentials of CD271+ and CD271− mesenchymal stromal cells were assessed by inducing osteogenic, adipogenic and chondrogenic in vitro differentiation. Compared to CD271+, CD271− mesenchymal stromal cells showed a lower proliferation rate and a decreased ability to give rise to osteocytes, adipocytes and chondrocytes. Furthermore, we observed that CD271+ mesenchymal stromal cells isolated from adipose tissue displayed a higher efficiency of proliferation and trilineage differentiation compared to CD271+ mesenchymal stromal cells isolated from bone marrow samples, although the CD271 expression levels were comparable. In conclusion, these data show that both the presence of CD271 antigen and the source of mesenchymal stromal cells represent important factors in determining the ability of the cells to proliferate and differentiate.

  3. Potential Effect of CD271 on Human Mesenchymal Stromal Cell Proliferation and Differentiation.

    Science.gov (United States)

    Calabrese, Giovanna; Giuffrida, Raffaella; Lo Furno, Debora; Parrinello, Nunziatina Laura; Forte, Stefano; Gulino, Rosario; Colarossi, Cristina; Schinocca, Luciana Rita; Giuffrida, Rosario; Cardile, Venera; Memeo, Lorenzo

    2015-07-09

    The Low-Affinity Nerve Growth Factor Receptor (LNGFR), also known as CD271, is a member of the tumor necrosis factor receptor superfamily. The CD271 cell surface marker defines a subset of multipotential mesenchymal stromal cells and may be used to isolate and enrich cells derived from bone marrow aspirate. In this study, we compare the proliferative and differentiation potentials of CD271+ and CD271- mesenchymal stromal cells. Mesenchymal stromal cells were isolated from bone marrow aspirate and adipose tissue by plastic adherence and positive selection. The proliferation and differentiation potentials of CD271+ and CD271- mesenchymal stromal cells were assessed by inducing osteogenic, adipogenic and chondrogenic in vitro differentiation. Compared to CD271+, CD271- mesenchymal stromal cells showed a lower proliferation rate and a decreased ability to give rise to osteocytes, adipocytes and chondrocytes. Furthermore, we observed that CD271+ mesenchymal stromal cells isolated from adipose tissue displayed a higher efficiency of proliferation and trilineage differentiation compared to CD271+ mesenchymal stromal cells isolated from bone marrow samples, although the CD271 expression levels were comparable. In conclusion, these data show that both the presence of CD271 antigen and the source of mesenchymal stromal cells represent important factors in determining the ability of the cells to proliferate and differentiate.

  4. Bone marrow stromal elements in murine leukemia; Decreased CSF-producing fibroblasts and normal IL-1 expression by macrophages

    Energy Technology Data Exchange (ETDEWEB)

    Ben-Ishay, Z. (Laboratory of Experimental Hematology, Department of Anatomy and Embryology, Hebrew University-Hadassah Medical School (Israel)); Barak, V. (Laboratory of Immunology, Department of Oncology, Hadassah University Hospital (Israel)); Shoshan, S. (Faculty of Dental Medicine, Connective Tissue Research Laboratory, Hebrew University, Jerusalem (Israel)); Prindull, G. (Department of Pediatrics, University of Gottingen, Gottingen (Germany, F.R.))

    1990-01-01

    A study of bone marrow stromal elements in murine acute myeloid leukemia (AML) was carried out. Our previous studies had indicated marrow stromal deficiency in murine AML. In the current investigation, separate stromal cells were cultured and the results obtained have shown that, while marrow stromal macrophages are normal in leukemia and express adequate amounts of IL-1, the fibroblasts are markedly reduced. However, if sufficient fibroblasts are pooled in vitro, they produce adequate amounts of CSF. Test of TNF{alpha} in leukemic cells CM, as possible cause of marrow stromal inhibition in leukemia, had not disclosed this cytokine. Further, it was observed that total body lethal irradiation of leukemic mice aggravates the stromal deficiency, confirming results of our previous investigations. It is concluded that bone marrow stromal deficiency in murine AML is due to decreased fibroblasts and, implicity, reduced CSF production. (author).

  5. A subset of high Gleason grade prostate carcinomas contain a large burden of prostate cancer syndecan-1 positive stromal cells.

    Science.gov (United States)

    Sharpe, Benjamin; Alghezi, Dhafer A; Cattermole, Claire; Beresford, Mark; Bowen, Rebecca; Mitchard, John; Chalmers, Andrew D

    2017-05-01

    There is a pressing need to identify prognostic and predictive biomarkers for prostate cancer to aid treatment decisions in both early and advanced disease settings. Syndecan-1, a heparan sulfate proteoglycan, has been previously identified as a potential prognostic biomarker by multiple studies at the tissue and serum level. However, other studies have questioned its utility. Anti-Syndecan-1 immunohistochemistry was carried out on 157 prostate tissue samples (including cancerous, adjacent normal tissue, and non-diseased prostate) from three independent cohorts of patients. A population of Syndecan-1 positive stromal cells was identified and the number and morphological parameters of these cells quantified. The identity of the Syndecan-1-positive stromal cells was assessed by multiplex immunofluorescence using a range of common cell lineage markers. Finally, the burden of Syndecan-1 positive stromal cells was tested for association with clinical parameters. We identified a previously unreported cell type which is marked by Syndecan-1 expression and is found in the stroma of prostate tumors and adjacent normal tissue but not in non-diseased prostate. We call these cells Prostate Cancer Syndecan-1 Positive (PCSP) cells. Immunofluorescence analysis revealed that the PCSP cell population did not co-stain with markers of common prostate epithelial, stromal, or immune cell populations. However, morphological analysis revealed that PCSP cells are often elongated and displayed prominent lamellipodia, suggesting they are an unidentified migratory cell population. Analysis of clinical parameters showed that PCSP cells were found with a frequency of 20-35% of all tumors evaluated, but were not present in non-diseased normal tissue. Interestingly, a subset of primary Gleason 5 prostate tumors had a high burden of PCSP cells. The current study identifies PCSP cells as a novel, potentially migratory cell type, which is marked by Syndecan-1 expression and is found in the stroma

  6. New therapeutic directions for advanced pancreatic cancer: cell cycle inhibitors, stromal modifiers and conjugated therapies.

    Science.gov (United States)

    Matera, Robert; Saif, Muhammad Wasif

    2017-09-01

    Pancreatic adenocarcinoma is a devastating malignancy with an extremely poor prognosis. These tumors progress rapidly and somewhat silently with few specific symptoms and are relatively resistant to chemotherapeutic agents. Many agents, including cell cycle inhibitors, are under development for the treatment of this cancer for which there are disappointingly few treatment options. Areas covered: Here we outline the existing approved treatments for advanced pancreatic disease and discuss a range of novel therapies currently under development including cell cycle inhibitors, stromal modifiers and conjugated therapies. We also describe the current state of the pancreatic cancer therapeutics market both past and future. Expert opinion: Despite the recent explosion of novel therapies with an array of unique targets, the core treatment of pancreatic cancer still with traditional cytotoxic agents with a few exceptions. However, as these novel treatments move through the pipeline, we are hopeful that there will soon be a number of effective options for patients with advanced pancreatic cancer.

  7. Label-free isolation of circulating tumor cells in microfluidic devices: Current research and perspectives.

    Science.gov (United States)

    Cima, Igor; Wen Yee, Chay; Iliescu, Florina S; Phyo, Wai Min; Lim, Kiat Hon; Iliescu, Ciprian; Tan, Min Han

    2013-01-01

    This review will cover the recent advances in label-free approaches to isolate and manipulate circulating tumor cells (CTCs). In essence, label-free approaches do not rely on antibodies or biological markers for labeling the cells of interest, but enrich them using the differential physical properties intrinsic to cancer and blood cells. We will discuss technologies that isolate cells based on their biomechanical and electrical properties. Label-free approaches to analyze CTCs have been recently invoked as a valid alternative to "marker-based" techniques, because classical epithelial and tumor markers are lost on some CTC populations and there is no comprehensive phenotypic definition for CTCs. We will highlight the advantages and drawbacks of these technologies and the status on their implementation in the clinics.

  8. Current Research of the Roles of IL-35 in Tumor Progression

    Directory of Open Access Journals (Sweden)

    Chongbiao HUANG

    2016-04-01

    Full Text Available Interleukin(IL-35 is a new member of the interleukin-12 superfamily. Since its first report in 2007, IL-35 rapidly became a research highlight in the field of immunology. Like other IL-12 superfamily members, IL-35 was a heterodimer which was composed of an α chain P35 and a β chain Epstein-Barr virus induced gene 3 (EBI3. Recent research work revealed two distinct roles of IL-35. Firstly, IL-35 is highly expressed in some kinds of inflammatory diseases and autoimmune diseases and plays import roles in the pathogenesis. Secondly, IL-35 is positively expressed in some cancers and plays some roles in the process of tumor progression. Here we demonstrate the structure and the signalling of IL-35. We reviewed the the roles of IL-35 in promoting tumor progression.

  9. Periductal stromal sarcoma of the breast with coexistent tuberculous mastitis

    Directory of Open Access Journals (Sweden)

    Bembem Khuraijam

    2017-01-01

    Full Text Available Periductal stromal sarcoma is a rare low-grade biphasic malignancy arising from periductal breast stroma. This tumor is distinct from phyllodes as it lacks the characteristic leaf-like architecture. Tuberculous mastitis is an uncommon infection seen rarely in the breast parenchyma. We present a rare association between the two diseases, which to the best of our knowledge is the first case reported so far.

  10. Embryonal carcinoma cell induction of miRNA and mRNA changes in co-cultured prostate stromal fibromuscular cells

    Science.gov (United States)

    VÊNCIO, ENEIDA F.; PASCAL, LAURA E.; PAGE, LAURA S.; DENYER, GARETH; WANG, AMY J.; RUOHOLA-BAKER, HANNELE; ZHANG, SHILE; WANG, KAI; GALAS, DAVID J.; LIU, ALVIN Y.

    2014-01-01

    The prostate stromal mesenchyme controls organ-specific development. In cancer, the stromal compartment shows altered gene expression compared to non-cancer. The lineage relationship between cancer-associated stromal cells and normal tissue stromal cells is not known. Nor is the cause underlying the expression difference. Previously, the embryonal carcinoma (EC) cell line, NCCIT, was used by us to study the stromal induction property. In the current study, stromal cells from non-cancer (NP) and cancer (CP) were isolated from tissue specimens and co-cultured with NCCIT cells in a trans-well format to preclude heterotypic cell contact. After 3 days, the stromal cells were analyzed by gene arrays for microRNA (miRNA) and mRNA expression. In co-culture, NCCIT cells were found to alter the miRNA and mRNA expression of NP stromal cells to one like that of CP stromal cells. In contrast, NCCIT had no significant effect on the gene expression of CP stromal cells. We conclude that the gene expression changes in stromal cells can be induced by diffusible factors synthesized by EC cells, and suggest that cancer-associated stromal cells represent a more primitive or less differentiated stromal cell type. PMID:20945389

  11. Mucinous sweat gland adenocarcinoma of the eyelid - current knowledge of a rare tumor.

    Science.gov (United States)

    Segal, Avichai; Segal, Nili; Gal, Andrew; Tumuluri, Krishna

    2010-12-01

    To review the medical literature on mucinous sweat gland adenocarcinoma of the eyelid (MSA) and present two new cases. Details of published case reports and small series (between 1971-2010) were evaluated and summarized including two patients diagnosed and treated at our institution. Data regarding age, gender, ethnicity, precise location, clinical presentation, treatment and follow up of each patient were collected. 25 reports describing 55 patients were found in the medical literature. The mean age was 61.3 years (30-87), 22(59%) were male and 28(80%) were Caucasian. In 23(44.2%) patients the lesion was in the lower lid, in 20(38.5%) in the upper lid, in 3(5.7%) involving both lids and in 6(11.6%) in a canthus. In 12(21.8%) patients a lesion with a benign diagnosis was previously excised from the same location. In 2 of them histological re-examination resulted in a diagnosis of MSA. Intraorbital involvement was found in 2(3.6%) patients. Regional lymph node metastasis was found in 2(4.4%) patients. Surgical excision was the treatment of choice using Mohs' micrographic-controlled excision technique in recent years. Radiotherapy was applied to 2 patients with clinical resolution in 1. Recurrence of the tumor was reported in 14(30%) patients. MSA is a rare tumor of the eyelid with no clinically distinguishing features. It should be suspected particularly with recurrent eyelid lesions and must be differentiated from metastatic disease. The tumor may extend into the orbit and metastasize regionally. Surgical removal with continued regular follow-up examination is the treatment of choice.

  12. Transition from low-grade endometrial stromal sarcoma to high-grade endometrial stromal sarcoma.

    Science.gov (United States)

    Ohta, Yoshiki; Suzuki, Takao; Omatsu, Mutsuko; Hamatani, Shigeharu; Shiokawa, Akira; Kushima, Miki; Ota, Hidekazu

    2010-07-01

    We report on a case of a primary low-grade endometrial stromal sarcoma (ESS) that progressed to a secondary high-grade ESS. In the secondary tumor, the immunohistochemical profile and focal tumor cell proliferation pattern suggested that this tumor was not truly undifferentiated, but possessed features of endometrial stroma. Low-grade ESS of our patient's primary tumor showed p53 protein overexpression, which is unusual in low-grade ESS, and her secondary high-grade ESS showed more prominent p53 immunoreactivity. This indicates that low-grade ESS that shows p53 immunoreactivity might progress to high-grade ESS, and it is considered that such cases of low-grade ESS should pay attention to the prognosis. Immunoreactivity for epidermal growth factor receptor was observed in both tumors, suggesting a relationship between the primary and secondary tumors in our case. Further study requires more immunohistochemical data for cases in which low-grade ESS transitions to high-grade ESS; in particular, data on epidermal growth factor receptor expression are necessary to define new therapeutic strategies for ESS.

  13. Cross-sectional imaging of biliary tumors: current clinical status and future developments

    Energy Technology Data Exchange (ETDEWEB)

    Zech, Christoph J.; Schoenberg, Stefan O.; Reiser, Maximilian; Helmberger, Thomas [Institute of Clinical Radiology, Munich University Hospitals-Grosshadern, Ludwig-Maximilians-University Munich, Marchioninistrasse 15, 81377, Munich (Germany)

    2004-07-01

    Extrahepatic cholangiocarcinoma, including hilar cholangiocarcinoma, is a relatively rare diagnosis. However, it frequently has been associated with major problems in diagnostics and clinical management from its first comprehensive description by Klatskin up until today. In this article, cholangiocarcinoma, representing the most common biliary tumor, as well as the differential diagnoses of benign and malignant biliary obstruction, will be discussed. The latest improvements of cross-sectional imaging modalities (sonography, CT, MRI and PET) and their diagnostic values for detection and staging will be displayed. A practical imaging-based diagnostic approach to obstructive biliary disease will be proposed. (orig.)

  14. Establishment and characterization of a cell line (OMC-9) originating from a human endometrial stromal sarcoma.

    Science.gov (United States)

    Kakuno, Yoshiteru; Yamada, Takashi; Mori, Hiroshi; Narabayashi, Isamu

    2008-05-01

    Cell lines are very useful for clinical and basic research. The establishment of uterine malignant tumor cell lines with unusual histology is especially important. We describe the establishment and characterization of a new human endometrial stromal sarcoma cell line of the uterus. The cell line OMC-9 was established from a tumor mass in the uterine body of a 55-year-old woman. Characteristics of the cell line studied include morphology, chromosome analysis, heterotransplantation, tumor markers and chemosensitivity. This cell line has grown well for 196 months and has been subcultured more than 50 times. Monolayer cultured cells are polygonal in shape, appear to be spindle-shaped or multipolar and have a tendency to pile up without contact inhibition. The cells exhibit a human karyotype with a modal chromosomal number in the diploid range. The cells were able to be transplanted into the subcutis of nude mice and produced tumors resembling the original tumor. OMC-9 cells produced tissue polypeptide antigen. Both CD10, a sensitive and diagnostically useful marker of endometrial stromal neoplasms, and vimentin were identified immunohistochemically in the original tumor and the heterotransplanted tumor. The cells were sensitive to actinomycin D, doxorubicin, carboplatin, cisplatin and etoposide, drugs used commonly in the treatment of gynecologic cancer. Only three reports of uterine endometrial stromal sarcoma cell lines have thus far been reported in the literature. OMC-9 is the first endometrial stromal sarcoma cell line in which CD10 expression and chemosensitivity have been identified.

  15. Primary Mesenteric Sertoli-Leydig Cell Tumor: A Case Report and Review of the Literature

    Directory of Open Access Journals (Sweden)

    Amel Trabelsi

    2008-01-01

    Full Text Available The occurrence of primary sex cord-stromal tumors at extraovarian sites is exceedingly rare. We report a new case of Sertoli-Leydig cell tumor in the mesentery of a 78-year-old woman who presented with occlusive syndrome and reviewed the previously reported cases of extraovarian sex cord-stromal tumors in the English literature.

  16. A rare cause of virilization; Ovarian steroid cell tumor, not otherwise specified (NOS)

    OpenAIRE

    Taşdemir, Nicel; Çelik, Cem; Abalı, Remzi; Aksu, Erson; Öznur, Meltem; Yılmaz, Murat

    2012-01-01

    Sex cord–stromal tumors account for 5% of ovarian tumors and 2% of malignant ovarian tumors. Steroid cell tumors (SCT), not otherwise specified (NOS), are rare sex cord–stromal tumors of the ovary and account for less than 0.1% of all ovarian tumors. We report a rare case of a post-menopausal woman presented with hirsutism, virilism and with findings of hyperestrogenism.

  17. Targeting Autophagy in the Tumor Microenvironment: New Challenges and Opportunities for Regulating Tumor Immunity

    Directory of Open Access Journals (Sweden)

    Bassam Janji

    2018-04-01

    Full Text Available Cancer cells evolve in the tumor microenvironment, which is now well established as an integral part of the tumor and a determinant player in cancer cell adaptation and resistance to anti-cancer therapies. Despite the remarkable and fairly rapid progress over the past two decades regarding our understanding of the role of the tumor microenvironment in cancer development, its precise contribution to cancer resistance is still fragmented. This is mainly related to the complexity of the “tumor ecosystem” and the diversity of the stromal cell types that constitute the tumor microenvironment. Emerging data indicate that several factors, such as hypoxic stress, activate a plethora of resistance mechanisms, including autophagy, in tumor cells. Hypoxia-induced autophagy in the tumor microenvironment also activates several tumor escape mechanisms, which effectively counteract anti-tumor immune responses mediated by natural killer and cytotoxic T lymphocytes. Therefore, strategies aiming at targeting autophagy in cancer cells in combination with other therapeutic strategies have inspired significant interest to overcome immunological tolerance and promote tumor regression. However, a number of obstacles still hamper the application of autophagy inhibitors in clinics. First, the lack of selectivity of the current pharmacological inhibitors of autophagy makes difficult to draw a clear statement about its effective contribution in cancer. Second, autophagy has been also described as an important mechanism in tumor cells involved in presentation of antigens to T cells. Third, there is a circumstantial evidence that autophagy activation in some innate immune cells may support the maturation of these cells, and it is required for their anti-tumor activity. In this review, we will address these aspects and discuss our current knowledge on the benefits and the drawbacks of targeting autophagy in the context of anti-tumor immunity. We believe that it is

  18. Stromal Expression of Hypoxia Regulated Proteins Is an Adverse Prognostic Factor in Colorectal Carcinomas

    Directory of Open Access Journals (Sweden)

    Arjen H. G. Cleven

    2007-01-01

    Full Text Available Background: Hypoxia modifies the phenotype of tumors in a way that promotes tumor aggressiveness and resistance towards chemotherapy and radiotherapy. However, the expression and influence of hypoxia-regulated proteins on tumor biology are not well characterized in colorectal tumors. We studied the role of protein expression of hypoxia-inducible factor (HIF-1α, HIF-2α, carbonic anhydrase 9 (CA9 and glucose transporter 1 (GLUT1 in patients with colorectal adenocarcinomas. Methods: Expression of HIF-1α, HIF-2α, CA9 and GLUT1 was quantified by immunohistochemistry in 133 colorectal adenocarcinomas. The expression of hypoxia markers was correlated with clinicopathological variables and overall patient survival. Results: Expression of these hypoxia markers was detected in the epithelial compartment of the tumor cells as well as in tumor-associated stromal cells. Although tumor cells frequently showed expression of one or more of the investigated hypoxia markers, no correlation among these markers or with clinical response was found. However, within the tumor stroma, positive correlations between the hypoxia markers HIF-2α, CA9 and GLUT1 were observed. Furthermore expression of HIF-2α and CA9 in tumor-associated stroma were both associated with a significantly reduced overall survival. In the Cox proportional hazard model, stromal HIF-2α expression was an independent prognostic factor for survival. Conclusion: These observations show, that expression of hypoxia regulated proteins in tumor-associated stromal cells, as opposed to their expression in epithelial tumor cells, is associated with poor outcome in colorectal cancer. This study suggests that tumor hypoxia may influence tumor-associated stromal cells in a way that ultimately contributes to patient prognosis.

  19. Epigenetic control of the tumor microenvironment

    Science.gov (United States)

    Marks, David L; Olson, Rachel LO; Fernandez-Zapico, Martin E

    2016-01-01

    Stromal cells of the tumor microenvironment have been shown to play important roles in both supporting and limiting cancer growth. The altered phenotype of tumor-associated stromal cells (fibroblasts, immune cells, endothelial cells etc.) is proposed to be mainly due to epigenetic dysregulation of gene expression; however, only limited studies have probed the roles of epigenetic mechanisms in the regulation of stromal cell function. We review recent studies demonstrating how specific epigenetic mechanisms (DNA methylation and histone post-translational modification-based gene expression regulation, and miRNA-mediated translational regulation) drive aspects of stromal cell phenotype, and discuss the implications of these findings for treatment of malignancies. We also summarize the effects of epigenetic mechanism-targeted drugs on stromal cells and discuss the consideration of the microenvironment response in attempts to use these drugs for cancer treatment. PMID:27700179

  20. Genetic engineering of mesenchymal stromal cells for cancer therapy: turning partners in crime into Trojan horses

    Directory of Open Access Journals (Sweden)

    Niess Hanno

    2016-09-01

    Full Text Available Mesenchymal stromal cells (MSCs are adult progenitor cells with a high migratory and differentiation potential, which influence a broad range of biological functions in almost every tissue of the body. Among other mechanisms, MSCs do so by the secretion of molecular cues, differentiation toward more specialized cell types, or influence on the immune system. Expanding tumors also depend on the contribution of MSCs to building a supporting stroma, but the effects of MSCs appear to go beyond the mere supply of connective tissues. MSCs show targeted “homing” toward growing tumors, which is then followed by exerting direct and indirect effects on cancer cells. Several research groups have developed novel strategies that make use of the tumor tropism of MSCs by engineering them to express a transgene that enables an attack on cancer growth. This review aims to familiarize the reader with the current knowledge about MSC biology, the existing evidence for MSC contribution to tumor growth with its underlying mechanisms, and the strategies that have been developed using MSCs to deploy an anticancer therapy.

  1. A single-center experience and review of the literature: 64 cases of phyllodes tumors to better understand risk factors and disease management.

    Science.gov (United States)

    Lightner, Amy L; Shurell, Elizabeth; Dawson, Nicole; Omidvar, Yasaman; Foster, Nova

    2015-03-01

    Phyllodes tumors of the breast are rare fibroepithelial tumors that are characterized as benign, borderline, or malignant based on cellular characteristics such as stromal overgrowth and number of mitoses. Currently, there is a lack of consensus on risk factors and management of patients with phyllodes tumors, which has led to variation in treatment patterns as well as patient outcomes across many institutions. This study seeks to understand the clinicopathologic features, risk factors for local and metastatic recurrence, and clinical outcomes of patients with phyllodes tumors to better define optimal treatment patterns.

  2. Carcinoma of the cervix. Value of dynamic magnetic resonance imaging in assessing early stromal invasion

    International Nuclear Information System (INIS)

    Kojima, Yumi; Aoki, Yoichi; Kase, Hiroaki; Kodama, Shoji; Tanaka, Kenichi

    1998-01-01

    The purpose of this study was to assess the accuracy of contrast-enhanced magnetic resonance imaging (dynamic MR imaging) in the evaluation of preinvasive and early invasive cancer of the cervix. Twenty-nine women with untreated squamous cell carcinoma of the cervix with either no stromal invasion or early stromal invasion underwent pretreatment MR imaging and dynamic MR imaging within 4 weeks of surgical evaluation. The images were evaluated for tumor detection and compared with results of histologic examination of the surgical specimens. The lesions in 17 cases with histologically proven stromal invasion of 4 mm or greater were detected with dynamic MR imaging, whereas lesions in only 8 of these cases were detected with T2 imaging. In 9 cases with stromal invasion between 4.0 mm and 5.0 mm, lesions were represented as early phase focal enhancement on dynamic MR images, but not detected on T2-weighted images. In the 12 cases with less than 4 mm stromal invasion, no lesions were visualized on either T2-weighted images or dynamic MR images, except in 1 case of glandular involvement without stromal invasion that appeared as enhancement on early-phase dynamic MR imaging. Dynamic MR imaging detected more lesions of early stromal invasion in pretreatment imaging for cervical cancer than nonenhanced MR imaging. (author)

  3. Bone marrow stromal cell : mediated neuroprotection for spinal cord repair

    NARCIS (Netherlands)

    Ritfeld, Gaby Jane

    2014-01-01

    Currently, there is no treatment available that restores anatomy and function after spinal cord injury. This thesis explores transplantation of bone marrow-derived mesenchymal stem cells (bone marrow stromal cells; BMSCs) as a therapeutic approach for spinal cord repair. BMSCs secrete neurotrophic

  4. Extracellular protease mRNAs are predominantly expressed in the stromal areas of microdissected mouse breast carcinomas

    DEFF Research Database (Denmark)

    Pedersen, Tanja Xenia; Pennington, Caroline J; Almholt, Kasper

    2005-01-01

    cells. We have now used laser capture microdissection and real-time PCR to quantify the mRNA expression of components of matrix-degrading proteolytic systems in cancer and stromal areas of mouse mammary tumors genetically induced by the polyoma virus middle T (PyMT) antigen. We examined the mRNA levels......Solid tumors synthesize a number of extracellular matrix-degrading proteases that are important for tumor progression. Based on qualitative in situ hybridization studies in human cancer tissue, a range of components involved in proteolysis appear to be expressed by stromal cells rather than cancer......RNAs for MMP-2, -3 and -13 in the PyMT tumors. Statistical analyses indicated that the quantitative expression patterns observed in cancer and stromal cells isolated from individual tumors from different PyMT mice are quite reproducible. The methodology described in this study provides excellent tools to study...

  5. Second harmonic generation reveals matrix alterations during breast tumor progression

    Science.gov (United States)

    Burke, Kathleen; Tang, Ping; Brown, Edward

    2013-03-01

    Alteration of the extracellular matrix in tumor stroma influences efficiency of cell locomotion away from the primary tumor into surrounding tissues and vasculature, thereby affecting metastatic potential. We study matrix changes in breast cancer through the use of second harmonic generation (SHG) of collagen in order to improve the current understanding of breast tumor stromal development. Specifically, we utilize a quantitative analysis of the ratio of forward to backward propagating SHG signal (F/B ratio) to monitor collagen throughout ductal and lobular carcinoma development. After detection of a significant decrease in the F/B ratio of invasive but not in situ ductal carcinoma compared with healthy tissue, the collagen F/B ratio is investigated to determine the evolution of fibrillar collagen changes throughout tumor progression. Results are compared with the progression of lobular carcinoma, whose F/B signature also underwent significant evolution during progression, albeit in a different manner, which offers insight into varying methods of tissue penetration and collagen manipulation between the carcinomas. This research provides insights into trends of stromal reorganization throughout breast tumor development.

  6. [Spheroids: A reference model for in vitro culture of solid tumors?

    Science.gov (United States)

    Larsen, Christian-Jacques

    2018-01-01

    The recognition that solid tumors are complex entities composed of the tumor cell mass itself and a stromal micro-environnement providing a variety of cells from the host (fibroblasts, endothelial cells, immune cells) led to recognize that this heterogeneity could not be recapitulated in vitro by conventional bidimensional (2-D) cultures. This justified numerous attempts to develop tridimensional (3-D) cultures that provided better tools for approaching tumor complexity and more convincing drug testing systems. Among various 3-D technologies, tumor spheroids are more likely suited to provide in vitro platforms for apprehending specific aspects of different processes specifically defining each tumor category as well as testing drug delivery systems. This review summarizes current features of multicellular tumor spheroids and their suitability for studying different aspects of cancer cell biology, patient-specific therapies and drug treatment. Copyright © 2017 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.

  7. Integration of chemotherapy into current treatment strategies for brain metastases from solid tumors

    International Nuclear Information System (INIS)

    Nieder, Carsten; Grosu, Anca L; Astner, Sabrina; Thamm, Reinhard; Molls, Michael

    2006-01-01

    Patients with brain metastases represent a heterogeneous group where selection of the most appropriate treatment depends on many patient- and disease-related factors. Eventually, a considerable proportion of patients are treated with palliative approaches such as whole-brain radiotherapy. Whole-brain radiotherapy in combination with chemotherapy has recently gained increasing attention and is hoped to augment the palliative effect of whole-brain radiotherapy alone and to extend survival in certain subsets of patients with controlled extracranial disease and good performance status. The randomized trials of whole-brain radiotherapy vs. whole-brain radiotherapy plus chemotherapy suggest that this concept deserves further study, although they failed to improve survival. However, survival might not be the most relevant endpoint in a condition, where most patients die from extracranial progression. Sometimes, the question arises whether patients with newly detected brain metastases and the indication for systemic treatment of extracranial disease can undergo standard systemic chemotherapy with the option of deferred rather than immediate radiotherapy to the brain. The literature contains numerous small reports on this issue, mainly in malignant melanoma, breast cancer, lung cancer and ovarian cancer, but very few sufficiently powered randomized trials. With chemotherapy alone, response rates were mostly in the order of 20–40%. The choice of chemotherapy regimen is often complicated by previous systemic treatment and takes into account the activity of the drugs in extracranial metastatic disease. Because the blood-brain barrier is partially disrupted in most macroscopic metastases, systemically administered agents can gain access to such tumor sites. Our systematic literature review suggests that both chemotherapy and radiochemotherapy for newly diagnosed brain metastases need further critical evaluation before standard clinical implementation. A potential chemotherapy

  8. Prostate stromal cells express the progesterone receptor to control cancer cell mobility.

    Directory of Open Access Journals (Sweden)

    Yue Yu

    Full Text Available Reciprocal interactions between epithelium and stroma play vital roles for prostate cancer development and progression. Enhanced secretions of cytokines and growth factors by cancer associated fibroblasts in prostate tumors create a favorable microenvironment for cancer cells to grow and metastasize. Our previous work showed that the progesterone receptor (PR was expressed specifically in prostate stromal fibroblasts and smooth muscle cells. However, the expression levels of PR and its impact to tumor microenvironment in prostate tumors are poorly understood.Immunohistochemistry assays are applied to human prostate tissue biopsies. Cell migration, invasion and proliferation assays are performed using human prostate cells. Real-time PCR and ELISA are applied to measure gene expression at molecular levels.Immunohistochemistry assays showed that PR protein levels were decreased in cancer associated stroma when compared with paired normal prostate stroma. Using in vitro prostate stromal cell models, we showed that conditioned media collected from PR positive stromal cells inhibited prostate cancer cell migration and invasion, but had minor suppressive impacts on cancer cell proliferation. PR suppressed the secretion of stromal derived factor-1 (SDF-1 and interlukin-6 (IL-6 by stromal cells independent to PR ligands. Blocking PR expression by siRNA or supplementation of exogenous SDF-1 or IL-6 to conditioned media from PR positive stromal cells counteracted the inhibitory effects of PR to cancer cell migration and invasion.Decreased expression of the PR in cancer associated stroma may contribute to the elevated SDF-1 and IL-6 levels in prostate tumors and enhance prostate tumor progression.

  9. Uterine sarcoma – current perspectives

    Directory of Open Access Journals (Sweden)

    Benson C

    2017-08-01

    Full Text Available Charlotte Benson,1 Aisha B Miah1,2 1Sarcoma Unit, Royal Marsden Hospital, 2Department of Radiotherapy and Imaging, The Institute of Cancer Research, London, UK Abstract: Uterine sarcomas comprise a group of rare tumors with differing tumor biology, natural history and response to treatment. Diagnosis is often made following surgery for presumed benign disease. Currently, preoperative imaging does not reliably distinguish between benign leiomyomas and other malignant pathology. Uterine leiomyosarcoma is the most common sarcoma, but other subtypes include endometrial stromal sarcoma (low grade and high grade, undifferentiated uterine sarcoma and adenosarcoma. Clinical trials have shown no definite survival benefit of adjuvant radiotherapy or chemotherapy and have been hampered by the rarity and heterogeneity of these disease types. There is a role of adjuvant treatment in carefully selected cases following multidisciplinary discussion at sarcoma reference centers. In patients with metastatic disease, systemic chemotherapy can then be considered. There is activity of a number of agents, including doxorubicin, trabectedin, gemcitabine-based chemotherapy, eribulin and pazopanib. Patients should be considered for clinical trial entry where possible. Close international collaboration is important to allow progress in this group of diseases. Keywords: sarcoma, leiomyosarcoma, endometrial stromal sarcoma, undifferentiated uterine sarcoma, leiomyoma

  10. Current approaches for avoiding the limitations of circulating tumor cells detection methods-implications for diagnosis and treatment of patients with solid tumors.

    Science.gov (United States)

    Kowalik, Artur; Kowalewska, Magdalena; Góźdź, Stanisław

    2017-07-01

    Eight million people die of cancer each year and 90% of deaths are caused by systemic disease. Circulating tumor cells (CTCs) contribute to the formation of metastases and thus are the subject of extensive research and an abiding interest to biotechnology and pharmaceutical companies. Recent technological advances have resulted in greatly improved CTC detection, enumeration, expansion, and culture methods. However, despite the fact that nearly 150 years have passed since the first detection and description of CTCs in human blood and enormous technological progress that has taken place in this field, especially within the last decade, few CTC detection methods have been approved for routine clinical use. This reflects the substantial methodological problems related to the nature of these cells, their heterogeneity, and diverse metastatic potential. Here, we provide an overview of CTC phenotypes, including the plasticity of CTCs and the relevance of inflammation and cell fusion phenomena for CTC biology. We also review the literature on CTC detection methodology-its recent improvements, clinical significance, and efforts of its clinical application in cancer patients management. At present, CTC detection remains a challenging diagnostic approach as a result of numerous current methodological limitations. This is especially problematic during the early stages of the disease due to the small numbers of CTCs released into the blood of cancer patients. Nonetheless, the rapid development of novel techniques of CTC detection and enumeration in peripheral blood is expected to expedite their implementation in the clinical setting. It is of utmost importance to understand the biology of CTCs and their distinct populations as a prerequisite for achieving this ultimate goal. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  11. Diagnosis and Treatment of Gastroenteropancreatic Neuroendocrine Tumors: Current Data on a Prospectively Collected, Retrospectively Analyzed Clinical Multicenter Investigation

    OpenAIRE

    Niederle, Martin B.; Niederle, Bruno

    2011-01-01

    Clinical information concerning diagnosis, symptoms, and treatment of 277 patients with gastrointestinal neuroendocrine tumors (including pancreatic tumors) diagnosed prospectively within 1 year were analyzed. Endoscopic and surgical techniques are the key to both correct diagnosis and effective treatment.

  12. Uterine sarcoma Part II—Uterine endometrial stromal sarcoma: The TAG systematic review

    Directory of Open Access Journals (Sweden)

    Huann-Cheng Horng

    2016-08-01

    Full Text Available Endometrial stromal tumors are rare uterine tumors (<1%. Four main categories include endometrial stromal nodule, low-grade endometrial stromal sarcoma (LG-ESS, high-grade endometrial stromal sarcoma (HG-ESS, and uterine undifferentiated sarcoma (UUS. This review is a series of articles discussing the uterine sarcomas. LG-ESS, a hormone-dependent tumor harboring chromosomal rearrangement, is an indolent tumor with a favorable prognosis, but characterized by late recurrences even in patients with Stage I disease, suggesting the requirement of a long-term follow-up. Patients with HG-ESS, based on the identification of YWHAE-NUTM2A/B (YWHAE-FAM22A/B gene fusion, typically present with advanced stage diseases and frequently have recurrences, usually within a few years after initial surgery. UUS is, a high-grade sarcoma, extremely rare, lacking a specific line of differentiation, which is a diagnosis of exclusion (the wastebasket category, which fails to fulfill the morphological and immunohistochemical criteria of translocation-positive ESS. Surgery is the main strategy in the management of uterine sarcoma. Due to rarity, complex biological characteristics, and unknown etiology and risk factors of uterine sarcomas, the role of adjuvant therapy is not clear. Only LG-ESS might respond to progestins or aromatase inhibitors.

  13. Marginal reticular cells: a stromal subset directly descended from the lymphoid tissue organizer

    Directory of Open Access Journals (Sweden)

    Tomoya eKatakai

    2012-07-01

    Full Text Available The architecture of secondary lymphoid organs (SLOs is supported by several nonhematopoietic stromal cells. Currently it is established that two distinct stromal subsets, follicular dendritic cells and fibroblastic reticular cells, play crucial roles in the formation of tissue compartments within SLOs, i.e., the follicle and T zone, respectively. Although stromal cells in the anlagen are essential for SLO development, the relationship between these primordial cells and the subsets in adulthood remains poorly understood. In addition, the roles of stromal cells in the entry of antigens into the compartments through some tissue structures peculiar to SLOs remain unclear. A recently identified stromal subset, marginal reticular cells (MRCs, covers the margin of SLOs that are primarily located in the outer edge of follicles and construct a unique reticulum. MRCs are closely associated with specialized endothelial or epithelial structures for antigen transport. The similarities in marker expression profiles and successive localization during development suggest that MRCs directly descend from organizer stromal cells in the anlagen. Therefore, MRCs are thought to be a crucial stromal component for the organization and function of SLOs.

  14. PREDICTORS OF OVERALL SURVIVAL IN PATIENTS WITH RECURRENT NON-SEMINOMATOUS GERMINAL TESTICULAR TUMORS ON CURRENT SECOND-LINE CHEMOTHERAPY

    Directory of Open Access Journals (Sweden)

    M. Yu. Fedyanin

    2010-01-01

    Full Text Available Objective: to define predictors that influence longevity in patients with recurrent non-seminomatous germinal testicular tumors (NGTT on standard second-line chemotherapy (CT including cisplatin and iphosphamide. Statistical analysis was performed using the statistical packages Graph Pad Prism 4.00 for Windows and SPSS 15.0 for Windows. Subjects and methods. Case history data were analyzed in 693 patients with disseminated NGTT who had received current CT and followed up at the Department of Clinical Pharmacology and CT, N.N. Blokhin Russian Cancer Research Center, Russian Academy of Medical Sciences. The median follow-up was 32 (range 3-215 months. The disease progressed in 181 (26% patients. Detailed information was available on the nature of second-line CT in only 138 patients. Half (71 (51.7% of the 138 patients had second-line CT including iphosphamide. Uni- and multivariate analyses were made to identify predictors that influence longevity in patients with recurrent NGTT on standard secondline CT including cisplatin and iphosphamide. Results. Five-year overall survival (OS was 32% (95% confidence interval 25-41%. The multivariate analysis showed the morphological pattern of a primary tumor (a yolk sac tumor component, a pre-induction CT lactate dehydrogenase (LDH level of ?d1.5 units of the upper normal range, progression during induction CT, and a pre-second-line CT LDH level of ?d 1000 U/l to be negative predictors. According to the number of negative factors, the patients were classified into 3 groups: 1 good prognosis [n = 10 (14% of the 71 patients], 100% 3-year OS; 2 intermediate prognosis (one negative factor [n = 33 (46.5% of the 71 patients], 50.2% 3-year OS; 3 poor prognosis (?d 2 negative factors, 6.7% 3-year OS. Conclusion. Standard iphosphamide-containing therapy enables all patients to be treated in the good prognosis group of those with recurrent NGTT. That fails to achieve such striking results in the intermediate and

  15. A study on the cellular stromal reaction and immunologic response of regional lymph nodes in gastric cancer

    International Nuclear Information System (INIS)

    Jyokoh, Hiroshi

    1986-01-01

    In an attempt to find a correlation between background factors and prognosis, cellular stromal reaction and PHA blastformation in the regional lymph nodes in gastric cancer were investigated in a total of 234 cases with advanced gastric cancer consisting of 104 patients who had undergone preoperative radiaiton therapy and 130 non-irradiated patients. The following results were obtained: 1) Interstitial matrix and fibrotic components around the gastric cancer cells proliferate. In addition, cellular components consisting mainly of lymphocytes appear in varied degrees. 2) In both non-irradiated and irradiated groups, there was no remarkable difference in the cellular stromal reaction among any major cancer sites. 3) In non-irradiated patients, no correlation existed between tumor diameters and cellular stromal reaction, while, in the irradiated cases, there were increases in the cellular stromal reaction where the tumor size is 5 cm or less. 4) In both non-irradiated and irradiated groups, cellular stromal reaction was more remarkable in highly differentiated carcinoma. 5) There were decreases in the cellular stromal reaction in ps(+) cases, of both non-irradiated and irradiated groups. 6) The cellular stromal reaction was remarkable in non-irradiated and irradiated patients who were found to be histologically negative in lymph node metastasis. 7) With the advance in staging, the cellular stromal reaction decreased in both irradiated and non-irradiated patients. 8) In both non-irradiated and irradiated groups, the cellular stromal reaction decreased in the patients who had shown vascular invasion. 9) PHA blastformation of the lymphocytes in lymph nodes of non-metastatic cases was more remarkable than that of metastatic cases, retaining high degrees of immunity. 10) In the non-metastatic patients in the lymph nodes outside the irradiated area, the lymphocytes in the lymph nodes demonstrated high degrees of PHA blastformation. (J.P.N.)

  16. Determinates of tumor response to radiation: Tumor cells, tumor stroma and permanent local control

    International Nuclear Information System (INIS)

    Li, Wende; Huang, Peigen; Chen, David J.; Gerweck, Leo E.

    2014-01-01

    Background and purpose: The causes of tumor response variation to radiation remain obscure, thus hampering the development of predictive assays and strategies to decrease resistance. The present study evaluates the impact of host tumor stromal elements and the in vivo environment on tumor cell kill, and relationship between tumor cell radiosensitivity and the tumor control dose. Material and methods: Five endpoints were evaluated and compared in a radiosensitive DNA double-strand break repair-defective (DNA-PKcs −/− ) tumor line, and its DNA-PKcs repair competent transfected counterpart. In vitro colony formation assays were performed on in vitro cultured cells, on cells obtained directly from tumors, and on cells irradiated in situ. Permanent local control was assessed by the TCD 50 assay. Vascular effects were evaluated by functional vascular density assays. Results: The fraction of repair competent and repair deficient tumor cells surviving radiation did not substantially differ whether irradiated in vitro, i.e., in the absence of host stromal elements and factors, from the fraction of cells killed following in vivo irradiation. Additionally, the altered tumor cell sensitivity resulted in a proportional change in the dose required to achieve permanent local control. The estimated number of tumor cells per tumor, their cloning efficiency and radiosensitivity, all assessed by in vitro assays, were used to predict successfully, the measured tumor control doses. Conclusion: The number of clonogens per tumor and their radiosensitivity govern the permanent local control dose

  17. Phyllodes Tumors of the Breast

    Science.gov (United States)

    Abusalem, Osama Turki; Al-Masri, Anwar

    2011-01-01

    Objective: To study all patients with phyllodes tumors of the breast which were diagnosed at King Hussien Medical Center and Prince Rashid Military Hospital between the 1st of may 2002 till January 2009. Methods: A total of 26 patients diagnosed to have phylloedes tumors were retrieved from the hospital records. All cases were analyzed and assessed in two main categories: demographical characteristics and histopathological parameters. The demographical characteristics included: sex and age of the patients, and tumor size while the histopathological aspects were divided into three subgroups: Benign, Borderline and Malignant tumors with its stromal components characteristics. All the histopathological reports for specimens sent by surgeons were reviewed by 2 senior pathologists. Statistical analysis was done by using Chi square and P-Value. Results: All our patients were females; their age range between 17-67 years, the mean patient age at presentation was 39 years. Out of the 26 patients diagnosed to have phyllodes tumor, 6 had breast-conserving therapy and 20 women had mastectomy. The types of Phyllodes tumors include: A-Benign phyllodes tumors (15 cases), B-Borderline phyllodes (7cases) and C-malignant phyllodes (4 cases). With significant values of benign tumors occurrence (pphyllodes tumors of the breast. The greatest dimension of the tumors ranged from 1 to 15 cm, with a mean of 5 cm. Approximately 73.1% of tumors were less or equal to 5 cm in the greatest dimension and 26.9% >5 cm. The duration of symptoms varied from one month to ten year.s Six patients had painful swellings, whereas in twenty patients the pain was absent. Four patients had recurrent tumors; the distinctive features of those with recurrent tumors were the histological findings of stromal over growth and the presence of positive resection margin. In our series, we found that three patients of those with recurrence discovered to have stromal over growth. While one only had a previous positive

  18. Imaging of gastrointestinal stromal tumour (GIST)

    Energy Technology Data Exchange (ETDEWEB)

    Lau, S. E-mail: laushunhk@yahoo.com.hk; Tam, K.F.; Kam, C.K.; Lui, C.Y.; Siu, C.W.; Lam, H.S.; Mak, K.L

    2004-06-01

    Gastrointestinal stromal tumour (GIST) represents the most common kind of mesenchymal tumour that arises from the alimentary tract. GIST is currently defined as a gastrointestinal tract mesenchymal tumour containing spindle cells (or less commonly epithelioid cells or rarely both) and showing CD117 (c-kit protein) positivity. Targeted molecular therapy of non-resectable GIST using imatinib, a specific tyrosine kinase receptor inhibitor, represents a real milestone in the management of solid malignancy. Imaging studies, both anatomical and functional, are playing an increasingly important role in management of patients with GIST. This review illustrates the radiological appearance of GISTs and the site-specific roles of each imaging tool. Clinical features and radiological differential diagnosis of GIST are also discussed.

  19. Follicular Thyroid Carcinoma Characterized by Abundant Stromal Components with Chondroid and Osseous Metaplasia in a Dog

    OpenAIRE

    KOBAYASHI, Ryosuke; YAMADA, Naoaki; KITAMORI, Takashi; KITAMORI, Fumiyo; SATO, Kazunari; DOI, Takuya; WAKO, Yumi; SATO, Junko; TSUCHITANI, Minoru

    2014-01-01

    ABSTRACT A dog developed a cervical mass, and computed tomography verified a mass surrounding the trachea with some pulmonary masses. Histopathologically, the cervical mass was composed of malignant neoplastic cells showing follicular appearance which reacted positive for thyroglobulin on immunohistochemistry. A characteristic feature of the tumor was abundant and metaplastic stromal components. Anastomosed collagenous tissues connecting to capsule of the tumor were abundant in the stroma. In...

  20. Synchronous Epithelioid Stromal Tumour and Lipoma in the Stomach

    Directory of Open Access Journals (Sweden)

    Nabeel Al-Brahim

    2003-01-01

    Full Text Available An 82-year-old man presented with upper gastrointestinal bleeding. A polypoid lesion of the distal stomach with focal ulceration was seen at endoscopy. This was treated by a partial gastrectomy. The resected stomach contained two separate tumours near the pylorus: a gastrointestinal stromal tumour (GIST and an adjacent lipoma. The literature includes case reports of synchronously occurring GIST and adenocarcinoma, GIST and mucosa-associated lymphoid tissue lymphoma and GIST and carcinoid tumour. Herein is the first case report of two distinct mesenchymal tumors coexisting in the stomach.

  1. Regulation of tumor invasion by interstitial fluid flow

    Science.gov (United States)

    Shieh, Adrian C.; Swartz, Melody A.

    2011-02-01

    The importance of the tumor microenvironment in cancer progression is undisputed, yet the significance of biophysical forces in the microenvironment remains poorly understood. Interstitial fluid flow is a nearly ubiquitous and physiologically relevant biophysical force that is elevated in tumors because of tumor-associated angiogenesis and lymphangiogenesis, as well as changes in the tumor stroma. Not only does it apply physical forces to cells directly, but interstitial flow also creates gradients of soluble signals in the tumor microenvironment, thus influencing cell behavior and modulating cell-cell interactions. In this paper, we highlight our current understanding of interstitial fluid flow in the context of the tumor, focusing on the physical changes that lead to elevated interstitial flow, how cells sense flow and how they respond to changes in interstitial flow. In particular, we emphasize that interstitial flow can directly promote tumor cell invasion through a mechanism known as autologous chemotaxis, and indirectly support tumor invasion via both biophysical and biochemical cues generated by stromal cells. Thus, interstitial fluid flow demonstrates how important biophysical factors are in cancer, both by modulating cell behavior and coupling biophysical and biochemical signals.

  2. Regulation of tumor invasion by interstitial fluid flow

    International Nuclear Information System (INIS)

    Shieh, Adrian C; Swartz, Melody A

    2011-01-01

    The importance of the tumor microenvironment in cancer progression is undisputed, yet the significance of biophysical forces in the microenvironment remains poorly understood. Interstitial fluid flow is a nearly ubiquitous and physiologically relevant biophysical force that is elevated in tumors because of tumor-associated angiogenesis and lymphangiogenesis, as well as changes in the tumor stroma. Not only does it apply physical forces to cells directly, but interstitial flow also creates gradients of soluble signals in the tumor microenvironment, thus influencing cell behavior and modulating cell–cell interactions. In this paper, we highlight our current understanding of interstitial fluid flow in the context of the tumor, focusing on the physical changes that lead to elevated interstitial flow, how cells sense flow and how they respond to changes in interstitial flow. In particular, we emphasize that interstitial flow can directly promote tumor cell invasion through a mechanism known as autologous chemotaxis, and indirectly support tumor invasion via both biophysical and biochemical cues generated by stromal cells. Thus, interstitial fluid flow demonstrates how important biophysical factors are in cancer, both by modulating cell behavior and coupling biophysical and biochemical signals

  3. Crioterapia de tumores renales: estado actual y desarrollos contemporáneos [= Cryotherapy for renal tumors: Current status and contemporary developments

    NARCIS (Netherlands)

    Rioja, J.; Tzortzis, V.; Mamoulakis, C.; Laguna, M. P.

    2010-01-01

    The proportion of renal tumors found incidentally dramatically increased in the past decade. More than half of them were diagnosed in patients over 70 years of age, a population with high associated comorbidity. Nephron-sparing minimally invasive surgical procedures are aimed at treating patients

  4. Radiologic Imaging Findings of Bilateral Infiltrating Pseudoangiomatous Stromal Hyperplasia of the Breasts:A Case Report

    Energy Technology Data Exchange (ETDEWEB)

    Go, Hee Sun; Jeh, Su Kyung [Dept. of Radiology, Kangnam Sacred Heart Hospital, College of Medicine, Hallym University, Seoul (Korea, Republic of)

    2013-04-15

    Pseudoangiomatous stromal hyperplasia (PASH), a rare benign lesion, shows the proliferation of the breast stromal tissue mimicking the low grade angiosarcoma (1-7). The most common mammographic and ultrasound finding of PASH is a circumscribed mass without calcification and it is difficult to distinguish from the phyllodes tumor and fibroadenoma (1-4, 8). Up to our knowledge, PASH presenting as rapid bilateral breast enlargement, as seen in our case, is very rare. In addition, several English medical literature were reported in this kind of manifestation of PASH (3, 4, 8). We described imaging findings of diffuse, infiltrating, and bilateral manifectation of PASH.

  5. Radiologic Imaging Findings of Bilateral Infiltrating Pseudoangiomatous Stromal Hyperplasia of the Breasts:A Case Report

    International Nuclear Information System (INIS)

    Go, Hee Sun; Jeh, Su Kyung

    2013-01-01

    Pseudoangiomatous stromal hyperplasia (PASH), a rare benign lesion, shows the proliferation of the breast stromal tissue mimicking the low grade angiosarcoma (1-7). The most common mammographic and ultrasound finding of PASH is a circumscribed mass without calcification and it is difficult to distinguish from the phyllodes tumor and fibroadenoma (1-4, 8). Up to our knowledge, PASH presenting as rapid bilateral breast enlargement, as seen in our case, is very rare. In addition, several English medical literature were reported in this kind of manifestation of PASH (3, 4, 8). We described imaging findings of diffuse, infiltrating, and bilateral manifectation of PASH.

  6. DCE-MRI using small-molecular and albumin-binding contrast agents in experimental carcinomas with different stromal content

    Energy Technology Data Exchange (ETDEWEB)

    Farace, Paolo; Merigo, Flavia; Fiorini, Silvia; Nicolato, Elena; Tambalo, Stefano; Daducci, Alessandro [Department of Morphological-Biomedical Sciences, Section of Anatomy and Histology, University of Verona, Verona (Italy); Degrassi, Anna [Nerviano Medical Sciences Institute, Milan (Italy); Sbarbati, Andrea [Department of Morphological-Biomedical Sciences, Section of Anatomy and Histology, University of Verona, Verona (Italy); Rubello, Domenico, E-mail: domenico.rubello@libero.it [Department of Radiology, Nuclear Medicine, Medical Physics, Services of Radiology and Nuclear Medicine, ' S. Maria della Misericordia' Hospital, Viale Tre Martiri 140, 45100 Rovigo (Italy); Marzola, Pasquina [Department of Morphological-Biomedical Sciences, Section of Anatomy and Histology, University of Verona, Verona (Italy)

    2011-04-15

    Objectives: To compare DCE-MRI experiments performed using a standard small-molecular (Gd-DTPA) and an albumin-binding (MS-325) contrast agent in two carcinoma models with different stromal content. Materials and methods: DU-145 or BXPC-3 cancer cells were subcutaneously injected into nude mice. DCE-MRI was performed by a bolus injection of Gd-DTPA or MS-325 about 2 weeks after inoculation. For quantitative analysis a volume of interest was manually drawn over each tumor. To address the heterogeneous enhancement, each tumor volume was then divided into the 20% most-enhancing and the remaining 80% least-enhancing fractions. Mean tumor enhancement was calculated over these selected tumor volumes and compared between tumor groups and contrast agents. Maps of differential enhancement, peak enhancement and time-to-peak were used for visual evaluation. CD31 and VEGF immunohistochemistry were performed in excised tumors. Results: In the 80% least-enhancing volume, at late time points of the dynamic scan, the mean enhancement elicited by MS-325 was higher in BXPC-3 than in DU-145 tumors. In the 20% most-enhancing volume, using either contrast agents, significant difference between the two tumors types were observed only early, while at later time points of the dynamic scan the difference were obscured by the faster washout observed in the BXPC-3 tumors. Enhancement maps confirmed that BXPC-3 tumors were characterized by marked washout rate using either contrast agent, particularly in the higher enhancing peripheral rim. With MS-325 this washout pattern appeared to be specific to the BXPC-3 carcinomas, since it was not observed in the DU-145 tumors. Finally, in both tumor types, MS-325 produced significantly higher enhancement than Gd-DTPA in the late phase of the dynamic scan. Ex vivo analysis confirmed the marked presence of aberrant infiltrative stroma in BXPC-3 tumors, in which tumor vessels were embedded. In all tumors the central portion was less viable and less

  7. Inhibition of Stromal PlGF Suppresses the Growth of Prostate Cancer Xenografts

    Directory of Open Access Journals (Sweden)

    Dietmar Abraham

    2013-09-01

    Full Text Available The growth and vascularization of prostate cancer is dependent on interactions between cancer cells and supporting stromal cells. The primary stromal cell type found in prostate tumors is the carcinoma-associated fibroblast, which produces placental growth factor (PlGF. PlGF is a member of the vascular endothelial growth factor (VEGF family of angiogenic molecules and PlGF mRNA levels increase after androgen deprivation therapy in prostate cancer. In this study, we show that PlGF has a direct dose-dependent proliferative effect on human PC-3 prostate cancer cells in vitro and fibroblast-derived PlGF increases PC-3 proliferation in co-culture. In xenograft tumor models, intratumoral administration of murine PlGF siRNA reduced stromal-derived PlGF expression, reduced tumor burden and decreased the number of Ki-67 positive proliferating cells associated with reduced vascular density. These data show that targeting stromal PlGF expression may represent a therapeutic target for the treatment of prostate cancer.

  8. An ex vivo co-culture model system to evaluate stromal-epithelial interactions in breast cancer.

    Science.gov (United States)

    Salameh, T S; Le, T T; Nichols, M B; Bauer, E; Cheng, J; Camarillo, I G

    2013-01-15

    Breast cancer is the most commonly diagnosed cancer among women worldwide. High breast cancer incidence and mortality rates, especially in obese patients, emphasize the need for a better biological understanding of this disease. Previous studies provide substantial evidence for a vital role of the local extracellular environment in multiple steps of tumor progression, including proliferation and invasion. Current evidence supports the role of adipocytes as an endocrine organ, which produces steroid hormones, pro-inflammatory cytokines and adipokines, such as leptin. To further define the role of the mammary microenvironment on tumorigenesis, we have developed an adipose-tumor epithelial cell co-culture system designed to reproduce the in vivo mammary environment. We validate this model through use of coherent anti-Stokes Raman scattering (CARS) microscopy, a label-free vibrational imaging technique. CARS analysis demonstrates the sustained viability of the adipocytes, and that mammary cancer cell morphology parallels that of tumors in vivo. Also, characterized was the influence of mammary adipose tissue on tumor cell growth and migration. Adipose tissue co-cultured with mammary tumor epithelial cells, in the absence of any serum or supplemental growth factors, resulted in substantial increases in growth and migration of tumor cells. In conclusion, this novel co-culture system provides an ideal model to study epithelial-stromal interactions in the mammary gland. Understanding the relationship between adipose tissue, the most abundant and least studied component of the breast stroma and tumor epithelial cells is critical to clarifying the influence of obesity on the development, progression and prognosis of breast cancer. Copyright © 2012 UICC.

  9. Human stromal (mesenchymal) stem cells

    DEFF Research Database (Denmark)

    Aldahmash, Abdullah; Zaher, Walid; Al-Nbaheen, May

    2012-01-01

    Human stromal (mesenchymal) stem cells (hMSC) represent a group of non-hematopoietic stem cells present in the bone marrow stroma and the stroma of other organs including subcutaneous adipose tissue, placenta, and muscles. They exhibit the characteristics of somatic stem cells of self......-renewal and multi-lineage differentiation into mesoderm-type of cells, e.g., to osteoblasts, adipocytes, chondrocytes and possibly other cell types including hepatocytes and astrocytes. Due to their ease of culture and multipotentiality, hMSC are increasingly employed as a source for cells suitable for a number...

  10. Tumor Budding, Micropapillary Pattern, and Polyploidy Giant Cancer Cells in Colorectal Cancer: Current Status and Future Prospects

    Directory of Open Access Journals (Sweden)

    Shiwu Zhang

    2016-01-01

    Full Text Available We previously reported that polyploid giant cancer cells (PGCGs induced by CoCl2 could form through endoreduplication or cell fusion. A single PGCC formed tumors in immunodeficient mice. PGCCs are also the key contributors to the cellular atypia and associate with the malignant grade of tumors. PGCCs have the properties of cancer stem cells and produce daughter cells via asymmetric cell division. Compared with diploid cancer cells, these daughter cells express less epithelial markers and acquire mesenchymal phenotype with importance in cancer development and progression. Tumor budding is generally recognized to correlate with a high recurrence rate, lymph node metastasis, chemoresistance, and poor prognosis of colorectal cancers (CRCs and is a good indicator to predict the metastasis and aggressiveness in CRCs. Micropapillary pattern is a special morphologic pattern and also associates with tumor metastasis and poor prognosis. There are similar morphologic features and molecular phenotypes among tumor budding, micropapillary carcinoma pattern, and PGCCs with their budding daughter cells and all of them show strong ability of tumor invasion and migration. In this review, we discuss the cancer stem cell properties of PGCCs, the molecular mechanisms of their regulation, and the relationships with tumor budding and micropapillary pattern in CRCs.

  11. Low Grade Endometrial Stromal Sarcoma: A Case Report

    Directory of Open Access Journals (Sweden)

    Reena Jain

    2015-01-01

    Full Text Available Endometrial stromal sarcoma (ESS is a rare malignant tumor of the endometrium, occurring in the age group of 40–50 years. We report a case of low-grade ESS in a 39-year-old woman, presenting as rapid enlargement of a uterine fibroid polyp associated with irregular and excessive vaginal bleeding. Polypectomy followed by pan hysterectomy was performed. Histopathological examination and immunohistochemistry confirmed LGESS. As the tumor is rarely encountered, management protocols are still questionable. In our case, we tried a different post-surgical protocol and the patient is being closely followed up. Although rare, ESS should be considered in the differential diagnosis of all women who present with a rapid enlargement of a uterine leiomyoma.

  12. Tumor Budding, Micropapillary Pattern, and Polyploidy Giant Cancer Cells in Colorectal Cancer: Current Status and Future Prospects

    OpenAIRE

    Zhang, Shiwu; Zhang, Dan; Yang, Zhengduo; Zhang, Xipeng

    2016-01-01

    We previously reported that polyploid giant cancer cells (PGCGs) induced by CoCl2 could form through endoreduplication or cell fusion. A single PGCC formed tumors in immunodeficient mice. PGCCs are also the key contributors to the cellular atypia and associate with the malignant grade of tumors. PGCCs have the properties of cancer stem cells and produce daughter cells via asymmetric cell division. Compared with diploid cancer cells, these daughter cells express less epithelial markers and acq...

  13. Long-range and short-range tumor-stroma networks synergistically contribute to tumor-associated epilepsy.

    Science.gov (United States)

    Mao, Xiao-Yuan; Tokay, Tursonjan; Zhou, Hong-Hao; Jin, Wei-Lin

    2016-05-31

    Epileptic seizures are frequently caused by brain tumors. Traditional anti-epileptic treatments do not acquire satisfactory responses. Preoperative and postoperative seizures seriously influence the quality of life of patients. Thus, tumor-associated epilepsy (TAE) is an important subject of the current research. The delineation of the etiology of epileptogenesis in patients with primary brain tumor may help to find the novel and effective drug targets for treating this disease. In this review, we describe the current status of treatment of TAE. More importantly, we focus on the factors that are involved in the functional connectivity between tumors and stromal cells. We propose that there exist two modes, namely, long-range and short-range modes, which likely trigger neuronal hyperexcitation and subsequent epileptic seizures. The long-range mode is referred to as factors released by tumors including glutamate and GABA, binding to the corresponding receptor on the cellular membrane and causing neuronal hyperactivity, while the short-range mode is considered to involve direct intracellular communication between tumor cells and stromas. Gap junctions and tunneling nanotube network are involved in cellular interconnections. Future investigations focused on those two modes may find a potential novel therapeutic target for treating TAE.

  14. Deficient repair regulatory response to injury in keratoconic stromal cells.

    Science.gov (United States)

    Cheung, Isabella My; McGhee, Charles Nj; Sherwin, Trevor

    2014-05-01

    Keratoconus manifests as a conical protrusion of the cornea and is characterised by stromal thinning. This causes debilitating visual impairment, which may necessitate corneal transplantation. Hypothetically, many of the pathological features in keratoconus may be manifestations of defects in wound healing; however, as the pathobiology remains unclear, therapeutic targets related to disease mechanisms are currently lacking. This study investigated the protein expression of cytokines which may control stromal wound healing and the effect of an induced secondary injury (SI) on stromal cells from ex vivo human keratoconus and control corneas. Total protein was extracted from stromal cells from human keratoconic and non-keratoconic central corneas (n = 12) with (+SI) and without (-SI) an ex vivo corneal incision wound. The levels of interleukin 1 alpha (IL-1α), fibroblast growth factor 2 (FGF-2), nerve growth factor beta (β-NGF), insulin-like growth factor 1 (IGF-1), tumour necrosis factor alpha (TNF-α), epidermal growth factor (EGF), transforming growth factor beta 1 (TGF-β1), platelet-derived growth factor (PDGF) and hepatocyte growth factor (HGF) were quantified using chemiluminescence-based immunoarrays. In stromal cells from -SI keratoconic corneas (compared with -SI normal corneas), the levels of IL-1α, IGF-1, TNF-α and TGF-β1 were increased and the levels of HGF and β-NGF were reduced. These alterations were also observed in +SI non-keratoconic corneas (compared with -SI non-keratoconic corneas). In stromal cells from +SI keratoconic corneas (compared with -SI keratoconic corneas), the quantities of IL-1α, FGF-2, TNF-a, EGF, TGF-a1 and PDGF were decreased. The repair-modulating milieu in keratoconic corneas appears comparable to that in wounded normal corneas. Moreover, wounded keratoconic corneas may be less capable of orchestrating a normal reparative response. These novel findings may improve our understanding of the pathobiology and may facilitate

  15. Paracrine interactions of cancer-associated fibroblasts, macrophages and endothelial cells: tumor allies and foes.

    Science.gov (United States)

    Ronca, Roberto; Van Ginderachter, Jo A; Turtoi, Andrei

    2018-01-01

    Tumor stroma is composed of many cellular subtypes, of which the most abundant are fibroblasts, macrophages and endothelial cells. During the process of tissue injury, these three cellular subtypes must coordinate their activity to efficiently contribute to tissue regeneration. In tumor, this mechanism is hijacked by cancer cells, which rewire the interaction of stromal cells to benefit tumor development. The present review aims at summarizing most relevant information concerning both pro-tumorigenic and anti-tumorigenic actions implicating the three stromal cell subtypes as well as their mutual interactions. Although stromal cells are generally regarded as tumor-supportive and at will manipulated by cancer cells, several novel studies point at many defaults in cancer cell-mediated stromal reprograming. Indeed, parts of initial tissue-protective and homeostatic functions of the stromal cells remain in place even after tumor development. Both tumor-supportive and tumor-suppressive functions have been well described for macrophages, whereas similar results are emerging for fibroblasts and endothelial cells. Recent success of immunotherapies have finally brought the long awaited proof that stroma is key for efficient tumor targeting. However, a better understanding of paracrine stromal interactions is needed in order to encourage drug development not only aiming at disruption of tumor-supportive communication but also re-enforcing, existing, tumor-suppressive mechanisms.

  16. LIF Mediates Proinvasive Activation of Stromal Fibroblasts in Cancer

    Directory of Open Access Journals (Sweden)

    Jean Albrengues

    2014-06-01

    Full Text Available Signaling crosstalk between tumor cells and fibroblasts confers proinvasive properties to the tumor microenvironment. Here, we identify leukemia inhibitory factor (LIF as a tumor promoter that mediates proinvasive activation of stromal fibroblasts independent of alpha-smooth muscle actin (α-SMA expression. We demonstrate that a pulse of transforming growth factor β (TGF-β establishes stable proinvasive fibroblast activation by inducing LIF production in both fibroblasts and tumor cells. In fibroblasts, LIF mediates TGF-β-dependent actomyosin contractility and extracellular matrix remodeling, which results in collective carcinoma cell invasion in vitro and in vivo. Accordingly, carcinomas from multiple origins and melanomas display strong LIF upregulation, which correlates with dense collagen fiber organization, cancer cell collective invasion, and poor clinical outcome. Blockade of JAK activity by Ruxolitinib (JAK inhibitor counteracts fibroblast-dependent carcinoma cell invasion in vitro and in vivo. These findings establish LIF as a proinvasive fibroblast producer independent of α-SMA and may open novel therapeutic perspectives for patients with aggressive primary tumors.

  17. Enhanced therapeutic agent delivery through magnetic resonance imaging-monitored focused ultrasound blood-brain barrier disruption for brain tumor treatment: an overview of the current preclinical status.

    Science.gov (United States)

    Liu, Hao-Li; Yang, Hung-Wei; Hua, Mu-Yi; Wei, Kuo-Chen

    2012-01-01

    Malignant glioma is a severe primary CNS cancer with a high recurrence and mortality rate. The current strategy of surgical debulking combined with radiation therapy or chemotherapy does not provide good prognosis, tumor progression control, or improved patient survival. The blood-brain barrier (BBB) acts as a major obstacle to chemotherapeutic treatment of brain tumors by severely restricting drug delivery into the brain. Because of their high toxicity, chemotherapeutic drugs cannot be administered at sufficient concentrations by conventional delivery methods to significantly improve long-term survival of patients with brain tumors. Temporal disruption of the BBB by microbubble-enhanced focused ultrasound (FUS) exposure can increase CNS-blood permeability, providing a promising new direction to increase the concentration of therapeutic agents in the brain tumor and improve disease control. Under the guidance and monitoring of MR imaging, a brain drug-delivery platform can be developed to control and monitor therapeutic agent distribution and kinetics. The success of FUS BBB disruption in delivering a variety of therapeutic molecules into brain tumors has recently been demonstrated in an animal model. In this paper the authors review a number of critical studies that have demonstrated successful outcomes, including enhancement of the delivery of traditional clinically used chemotherapeutic agents or application of novel nanocarrier designs for actively transporting drugs or extending drug half-lives to significantly improve treatment efficacy in preclinical animal models.

  18. Tumor radiosensitizers - current status of development of various approaches: Report of an International Atomic Energy Agency meeting

    DEFF Research Database (Denmark)

    Horsman, Michael Robert; Bohm, Lothar; Margison, Geoffrey P.

    2006-01-01

    PURPOSE: The International Atomic Energy Agency (IAEA) held a Technical Meeting of Consultants to (1) discuss a selection of relatively new agents, not those well-established in clinical practice, that operated through a variety of mechanisms to sensitize tumors to radiation and (2) to compare...... contrasted with new molecular antisense and gene therapy strategies. All the drugs discussed have previously been shown to act as tumor cell radiosensitizers or to kill hypoxic cells present in tumors. CONCLUSION: Specific recommendations were made for more preclinical studies with certain of the agents...... and for clinical trials that would be suitable for industrialized countries, as well as trials that were considered more appropriate for developing countries.PURPOSE: The International Atomic Energy Agency (IAEA) held a Technical Meeting of Consultants to (1) discuss a selection of relatively new agents, not those...

  19. [Mesenchymal gastric tumor--not always GIST].

    Science.gov (United States)

    Grosse-Holz, M; Sackmann, M; Seitz, G

    2015-02-01

    The correct histopathological classification of a gastric mesenchymal tumor as a schwannoma is essential because in contrast to gastrointestinal stromal tumors (GIST) it is a definitive benign neoplasm which can be sufficiently treated by in sano (R0) resection. A (partial) gastrectomy is unnecessary. A clear radiological or sonographical differentiation between a schwannoma and GIST is not possible. The histomorphological and immunohistochemical features of this tumor entity are described.

  20. Stromal and Epithelial Caveolin-1 Both Confer a Protective Effect Against Mammary Hyperplasia and Tumorigenesis : Caveolin-1 Antagonizes Cyclin D1 Function in Mammary Epithelial Cells

    OpenAIRE

    Williams, Terence M.; Sotgia, Federica; Lee, Hyangkyu; Hassan, Ghada; Di Vizio, Dolores; Bonuccelli, Gloria; Capozza, Franco; Mercier, Isabelle; Rui, Hallgeir; Pestell, Richard G.; Lisanti, Michael P.

    2006-01-01

    Here, we investigate the role of caveolin-1 (Cav-1) in breast cancer onset and progression, with a focus on epithelial-stromal interactions, ie, the tumor microenvironment. Cav-1 is highly expressed in adipocytes and is abundant in mammary fat pads (stroma), but it remains unknown whether loss of Cav-1 within mammary stromal cells affects the differentiated state of mammary epithelia via paracrine signaling. To address this issue, we characterized the development of the mammary ductal system ...

  1. Are mesenchymal stromal cells immune cells?

    NARCIS (Netherlands)

    M.J. Hoogduijn (Martin)

    2015-01-01

    textabstractMesenchymal stromal cells (MSCs) are considered to be promising agents for the treatment of immunological disease. Although originally identified as precursor cells for mesenchymal lineages, in vitro studies have demonstrated that MSCs possess diverse immune regulatory capacities.

  2. Follicular thyroid carcinoma characterized by abundant stromal components with chondroid and osseous metaplasia in a dog.

    Science.gov (United States)

    Kobayashi, Ryosuke; Yamada, Naoaki; Kitamori, Takashi; Kitamori, Fumiyo; Sato, Kazunari; Doi, Takuya; Wako, Yumi; Sato, Junko; Tsuchitani, Minoru

    2014-08-01

    A dog developed a cervical mass, and computed tomography verified a mass surrounding the trachea with some pulmonary masses. Histopathologically, the cervical mass was composed of malignant neoplastic cells showing follicular appearance which reacted positive for thyroglobulin on immunohistochemistry. A characteristic feature of the tumor was abundant and metaplastic stromal components. Anastomosed collagenous tissues connecting to capsule of the tumor were abundant in the stroma. In parts of the collagenous tissues, mature cartilages and bones were continuously formed. There was no cellular atypia or invasion in the components. We diagnosed this case as follicular thyroid carcinoma with metaplastic stroma. This is the first case report that characterizes stromal components with chondroid and osseous metaplasia in a canine thyroid carcinoma.

  3. Ultrasonographic findings of low-grade endometrial stromal sarcoma of the uterus with a focus on cystic degeneration

    Energy Technology Data Exchange (ETDEWEB)

    Park, Ga Eun; Rha, Sung Eun; Oh, Soon Nam; Lee, Ah Won; Lee, Keun Ho; Kim, Mee Ran [Seoul St. Mary' s Hospital, College of Medicine, The Catholic University of Korea, Seoul (Korea, Republic of)

    2016-03-15

    The goal of this study was to perform a retrospective analysis of the ultrasonographic findings associated with low-grade endometrial stromal sarcoma. Ten pathologically confirmed cases of low-grade endometrial stromal sarcoma at our institution from January 2007 to April 2014 were retrospectively reviewed. All patients underwent a preoperative transvaginal ultrasound. Two radiologists came to a consensus regarding the location, size, margin, and echogenicity of the tumor, as well as the presence of intratumoral cystic degeneration and its extent and configuration. Low-grade endometrial stromal sarcoma manifested as an intramural mass protruding into the endometrial cavity (n=6) or as a purely intramural mass (n=4). The maximal diameter of the lesion ranged from 4 to 9.1 cm (mean, 6.2 cm). The imaging features of low-grade endometrial stromal sarcoma were variable: six cases involved predominantly solid masses containing cystic degeneration, one was a predominantly unilocular cystic mass, two were ill-defined infiltrative solid masses, and one was a well-defined solid mass. Among the seven cases with internal cystic degeneration, five patients showed a multiseptated cystic area or a cystic area with multiple small clusters, while a unilocular cystic area within the tumor was found in two patients. Low-grade endometrial stromal sarcoma is associated with variable ultrasonographic findings with regard to the location, margin, and configuration of the lesion. Multiseptated cystic areas and multiple small areas of cystic degeneration are common.

  4. High incidence of MYCN amplification in a Moroccan series of neuroblastic tumors: comparison to current biological data.

    Science.gov (United States)

    Tabyaoui, Imane; Tahiri-Jouti, Nadia; Serhier, Zineb; El Maani, Khadija; Cherkaoui, Siham; Al Zemmouri, Mounia; Othmani, Mohamed B; Zamiati, Soumaya

    2013-06-01

    MYCN protooncogene status was assessed for the first time in Morocco in peripheral neuroblastic tumors, including neuroblastoma, ganglioneuroblastoma, and ganglioneuroma. Correlations with age at diagnosis, stage, mitosis-karyorrhexis index, differentiation, and Shimada histology were evaluated. Thirty-six formalin-fixed, paraffin-embedded peripheral neuroblastic tumor tissue specimens collected between 2007 and 2010 from the Pathology Department were assessed for MYCN amplification using fluorescence in situ hybridization. MYCN amplification was found in 27.8% of cases. An association of MYCN amplification with unfavorable Shimada grading, higher mitosis-karyorrhexis index, and undifferentiated morphologic phenotype was found. We found no correlation with older age, advanced stage, or the presence of metastasis. Our results suggested that the presence of MYCN amplification is a strong biological indicator of a poor outcome and aggressive disease in neuroblastoma and nodular ganglioneuroblastoma.

  5. Ten-Year Progression-Free and Overall Survival in Patients With Unresectable or Metastatic GI Stromal Tumors: Long-Term Analysis of the European Organisation for Research and Treatment of Cancer, Italian Sarcoma Group, and Australasian Gastrointestinal Trials Group Intergroup Phase III Randomized Trial on Imatinib at Two Dose Levels.

    Science.gov (United States)

    Casali, Paolo G; Zalcberg, John; Le Cesne, Axel; Reichardt, Peter; Blay, Jean-Yves; Lindner, Lars H; Judson, Ian R; Schöffski, Patrick; Leyvraz, Serge; Italiano, Antoine; Grünwald, Viktor; Pousa, Antonio Lopez; Kotasek, Dusan; Sleijfer, Stefan; Kerst, Jan M; Rutkowski, Piotr; Fumagalli, Elena; Hogendoorn, Pancras; Litière, Saskia; Marreaud, Sandrine; van der Graaf, Winette; Gronchi, Alessandro; Verweij, Jaap

    2017-05-20

    Purpose To report on the long-term results of a randomized trial comparing a standard dose (400 mg/d) versus a higher dose (800 mg/d) of imatinib in patients with metastatic or locally advanced GI stromal tumors (GISTs). Patients and Methods Eligible patients with advanced CD117-positive GIST from 56 institutions in 13 countries were randomly assigned to receive either imatinib 400 mg or 800 mg daily. Patients on the 400-mg arm were allowed to cross over to 800 mg upon progression. Results Between February 2001 and February 2002, 946 patients were accrued. Median age was 60 years (range, 18 to 91 years). Median follow-up time was 10.9 years. Median progression-free survival times were 1.7 and 2.0 years in the 400- and 800-mg arms, respectively (hazard ratio, 0.91; P = .18), and median overall survival time was 3.9 years in both treatment arms. The estimated 10-year progression-free survival rates were 9.5% and 9.2% for the 400- and 800-mg arms, respectively, and the estimated 10-year overall survival rates were 19.4% and 21.5%, respectively. At multivariable analysis, age (< 60 years), performance status (0 v ≥ 1), size of the largest lesion (smaller), and KIT mutation (exon 11) were significant prognostic factors for the probability of surviving beyond 10 years. Conclusion This trial was carried out on a worldwide intergroup basis, at the beginning of the learning curve of the use of imatinib, in a large population of patients with advanced GIST. With a long follow-up, 6% of patients are long-term progression free and 13% are survivors. Among clinical prognostic factors, only performance status, KIT mutation, and size of largest lesion predicted long-term outcome, likely pointing to a lower burden of disease. Genomic and/or immune profiling could help understand long-term survivorship. Addressing secondary resistance remains a therapeutic challenge.

  6. [What future for circulating tumor DNA? Current data and prospects in colorectal, non-small cell lung and pancreatic cancers].

    Science.gov (United States)

    Pietrasz, Daniel; Pécuchet, Nicolas; Fabre, Elizabeth; Blons, Hélène; Chevalier, Line; Taly, Valérie; Laurent-Puig, Pierre; Bachet, Jean-Baptiste

    2016-01-01

    Ten years after the discovery of the predictive value of KRAS status for anti-EGFR antibodies, other genes involved in oncogenesis and therapeutic responses were identified and are now systematically sought. Molecular diagnosis often requires invasive procedures, sometimes iatrogenic, and is limited by feasibility problems, quantity and quality of samples. Identifying these mutations from blood biomarkers would reduce costs and diagnostic delay. The circulating tumor DNA (ctDNA) is one of the most promising blood biomarkers. In this review, we report and discuss the latest results obtained with ctDNA in colorectal cancer, non-small cell lung cancer, and adenocarcinoma of the pancreas. If the methods highlighting appear very heterogeneous, the correlation between mutations found in tumor and those identified in the blood exceeds 95 % specificity in numerous studies. The detection sensitivity is in turn strongly related to tumor stage patients. The presence of ctDNA appears as a prognostic factor for progression-free survival and overall survival. Finally, recent studies have shown that the changing rate ctDNA during systemic treatments had a predictive value for therapeutic efficacy. These results allow to consider the use of ctDNA in monitoring patients to identify early recurrence or progression. Copyright © 2015 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.

  7. Gastric Schwannoma: A Tumor Must Be Included in Differential Diagnoses of Gastric Submucosal Tumors.

    Science.gov (United States)

    Hu, Bao-Guang; Wu, Feng-Jie; Zhu, Jun; Li, Xiao-Mei; Li, Yu-Ming; Feng, Yan; Li, He-Sheng

    2017-01-01

    Gastric schwannoma (GS) is a rare neoplasm of the stomach. It accounts for 0.2% of all gastric tumors and is mostly benign, slow-growing, and asymptomatic. Due to its rarity, GS is not widely recognized by clinicians, and the precise differential diagnosis between GS and other gastric submucosal tumors remains difficult preoperatively. The present study reports a case of GS misdiagnosed as gastrointestinal stromal tumor and reviews the clinical, imaging, and pathological features, treatment, and follow-up of 221 patients with GS previously reported in the English literature. Although GS is rare, the case reported in the current study highlights the importance of including GS in differential diagnoses of gastric submucosal tumors. Furthermore, the findings of the review suggest that although many cases are asymptomatic, the most common symptoms are abdominal pain or discomfort, not gastrointestinal bleeding, and malignant GSs present with clinical symptoms more commonly. Although large-sample multicenter studies on the efficacy, safety, and oncological outcomes of minimally invasive techniques are required, the findings presented herein may be helpful for clinicians when diagnosing or treating GS.

  8. Gastric Schwannoma: A Tumor Must Be Included in Differential Diagnoses of Gastric Submucosal Tumors

    Directory of Open Access Journals (Sweden)

    Bao-guang Hu

    2017-01-01

    Full Text Available Gastric schwannoma (GS is a rare neoplasm of the stomach. It accounts for 0.2% of all gastric tumors and is mostly benign, slow-growing, and asymptomatic. Due to its rarity, GS is not widely recognized by clinicians, and the precise differential diagnosis between GS and other gastric submucosal tumors remains difficult preoperatively. The present study reports a case of GS misdiagnosed as gastrointestinal stromal tumor and reviews the clinical, imaging, and pathological features, treatment, and follow-up of 221 patients with GS previously reported in the English literature. Although GS is rare, the case reported in the current study highlights the importance of including GS in differential diagnoses of gastric submucosal tumors. Furthermore, the findings of the review suggest that although many cases are asymptomatic, the most common symptoms are abdominal pain or discomfort, not gastrointestinal bleeding, and malignant GSs present with clinical symptoms more commonly. Although large-sample multicenter studies on the efficacy, safety, and oncological outcomes of minimally invasive techniques are required, the findings presented herein may be helpful for clinicians when diagnosing or treating GS.

  9. Clinicopathologic features of ovarian neoplasms with emphasis on borderline ovarian tumors: an institutional perspective.

    Science.gov (United States)

    Hashmi, Atif Ali; Hussain, Zubaida Fida; Bhagwani, Aneel Roy; Edhi, Muhammad Muzzammil; Faridi, Naveen; Hussain, Syed Danish; Khan, Mehmood

    2016-04-06

    Ovarian cancer is the most lethal gynecologic malignancy and it represents third most common malignancy in Karachi (after breast and oral cancer). Due to lack of well established cancer registry in our country, changing trends of ovarian tumors has not been determined. Therefore we aimed to establish the current trends and classification of ovarian tumors in our setup according to latest WHO guidelines. We retrospectively analyzed 162 cases of ovarian tumors that underwent surgical resection from January 2009 till December 2014. Specimens were received in histopathology department, Liaquat National hospital and cases were examined by senior histopathologists and classified according to latest WHO guidelines. Various histopathologic parameters including capsular invasion, omental and lymph node meatstasis along with uterine and fallopian tube involvement were determined apart from tumor type and grade. Mean age at diagnosis was 35.8 years (± 15.5). surface epithelial tumors were most common, 109 cases (67.2%) followed by germ cell tumors, 44 cases (27.1%) and sex cord stromal tumors, 8 cases (4.9%). Serous tumors were most common surface epithelial tumors with 90% benign morphology. On the other hand, mucinous tumors showed a higher percentage of borderline and malignant features (16.7 and 14.6% respectively). Higher incidence of capsular invasion and omental metastasis was noted in endometroid and serous carcinoma compared to mucinous tumors. We noted a higher frequency of young age ovarian cancers in our set up. Serous and endometroid carcinomas were found to be associated with adverse prognostic factors like capsular invasion and omental metastasis. Moreover a significantly higher proportion of ovarian tumors constitute mucinous histology including borderline tumors. Whether this represents a changing trend towards biology of these tumors in this part of the world needs to be uncovered by further studies.

  10. A stable explant culture of HER2/neu invasive carcinoma supported by alpha-Smooth Muscle Actin expressing stromal cells to evaluate therapeutic agents

    Directory of Open Access Journals (Sweden)

    Piechocki Marie P

    2008-04-01

    Full Text Available Abstract Background To gain a better understanding of the effects of therapeutic agents on the tumor microenvironment in invasive cancers, we developed a co-culture model from an invasive lobular carcinoma. Tumor cells expressing HER2/neu organize in nests surrounded by alpha-Smooth Muscle Actin (α-SMA expressing tumor stroma to resemble the morphology of an invading tumor. This co-culture, Mammary Adenocarcinoma Model (MAM-1 maintains a 1:1 ratio of HER2/neu positive tumor cells to α-SMA-reactive stromal cells and renews this configuration for over 20 passages in vitro. Methods We characterized the cellular elements of the MAM-1 model by microarray analysis, and immunocytochemistry. We developed flow cytometric assays to evaluate the relative responses of the tumor and stroma to the tyrosine kinase inhibitor, Iressa. Results The MAM-1 gene expression profile contains clusters that represent the ErbB-2 breast cancer signature and stroma-specific clusters associated with invasive breast cancers. The stability of this model and the ability to antigenically label the tumor and stromal fractions allowed us to determine the specificity of Iressa, a receptor tyrosine kinase inhibitor, for targeting the tumor cell population. Treatment resulted in a selective dose-dependent reduction in phospho-pMEK1/2 and pp44/42MAPK in tumor cells. Within 24 h the tumor cell fraction was reduced 1.9-fold while the stromal cell fraction increased >3-fold, consistent with specific reductions in phospho-pp44/42 MAPK, MEK1/2 and PCNA in tumor cells and reciprocal increases in the stromal cells. Erosion of the tumor cell nests and augmented growth of the stromal cells resembled a fibrotic response. Conclusion This model demonstrates the specificity of Iressa for HER2/neu expressing tumor cells versus the tumor associated myofibroblasts and is appropriate for delineating effects of therapy on signal transduction in the breast tumor microenvironment and improving

  11. A stable explant culture of HER2/neu invasive carcinoma supported by alpha-Smooth Muscle Actin expressing stromal cells to evaluate therapeutic agents

    International Nuclear Information System (INIS)

    Piechocki, Marie P

    2008-01-01

    To gain a better understanding of the effects of therapeutic agents on the tumor microenvironment in invasive cancers, we developed a co-culture model from an invasive lobular carcinoma. Tumor cells expressing HER2/neu organize in nests surrounded by alpha-Smooth Muscle Actin (α-SMA) expressing tumor stroma to resemble the morphology of an invading tumor. This co-culture, Mammary Adenocarcinoma Model (MAM-1) maintains a 1:1 ratio of HER2/neu positive tumor cells to α-SMA-reactive stromal cells and renews this configuration for over 20 passages in vitro. We characterized the cellular elements of the MAM-1 model by microarray analysis, and immunocytochemistry. We developed flow cytometric assays to evaluate the relative responses of the tumor and stroma to the tyrosine kinase inhibitor, Iressa. The MAM-1 gene expression profile contains clusters that represent the ErbB-2 breast cancer signature and stroma-specific clusters associated with invasive breast cancers. The stability of this model and the ability to antigenically label the tumor and stromal fractions allowed us to determine the specificity of Iressa, a receptor tyrosine kinase inhibitor, for targeting the tumor cell population. Treatment resulted in a selective dose-dependent reduction in phospho-pMEK1/2 and pp44/42MAPK in tumor cells. Within 24 h the tumor cell fraction was reduced 1.9-fold while the stromal cell fraction increased >3-fold, consistent with specific reductions in phospho-pp44/42 MAPK, MEK1/2 and PCNA in tumor cells and reciprocal increases in the stromal cells. Erosion of the tumor cell nests and augmented growth of the stromal cells resembled a fibrotic response. This model demonstrates the specificity of Iressa for HER2/neu expressing tumor cells versus the tumor associated myofibroblasts and is appropriate for delineating effects of therapy on signal transduction in the breast tumor microenvironment and improving strategies that can dually or differentially target the tumor and stromal

  12. Modulation of Tumor Tolerance in Primary Central Nervous System Malignancies

    Directory of Open Access Journals (Sweden)

    Theodore S. Johnson

    2012-01-01

    Full Text Available Central nervous system tumors take advantage of the unique immunology of the CNS and develop exquisitely complex stromal networks that promote growth despite the presence of antigen-presenting cells and tumor-infiltrating lymphocytes. It is precisely this immunological paradox that is essential to the survival of the tumor. We review the evidence for functional CNS immune privilege and the impact it has on tumor tolerance. In this paper, we place an emphasis on the role of tumor-infiltrating myeloid cells in maintaining stromal and vascular quiescence, and we underscore the importance of indoleamine 2,3-dioxygenase activity as a myeloid-driven tumor tolerance mechanism. Much remains to be discovered regarding the tolerogenic mechanisms by which CNS tumors avoid immune clearance. Thus, it is an open question whether tumor tolerance in the brain is fundamentally different from that of peripheral sites of tumorigenesis or whether it simply stands as a particularly strong example of such tolerance.

  13. A Rare Case of Mesenteric Gastrointestinal Stromal Tumor ...

    African Journals Online (AJOL)

    regions. Abdominal ultrasound showed 18 cm × 15 cm mass with solid and cystic components arising from small bowel mesentery with loops of bowel adherent to it. A clinical diagnosis of mesenteric cyst with small bowel obstruction was made. Emergency laparotomy done for acute abdomen showed a huge mass of.

  14. Metabolic cooperation between cancer and non-cancerous stromal cells is pivotal in cancer progression.

    Science.gov (United States)

    Lopes-Coelho, Filipa; Gouveia-Fernandes, Sofia; Serpa, Jacinta

    2018-02-01

    The way cancer cells adapt to microenvironment is crucial for the success of carcinogenesis, and metabolic fitness is essential for a cancer cell to survive and proliferate in a certain organ/tissue. The metabolic remodeling in a tumor niche is endured not only by cancer cells but also by non-cancerous cells that share the same microenvironment. For this reason, tumor cells and stromal cells constitute a complex network of signal and organic compound transfer that supports cellular viability and proliferation. The intensive dual-address cooperation of all components of a tumor sustains disease progression and metastasis. Herein, we will detail the role of cancer-associated fibroblasts, cancer-associated adipocytes, and inflammatory cells, mainly monocytes/macrophages (tumor-associated macrophages), in the remodeling and metabolic adaptation of tumors.

  15. Stromal Androgen Receptor Roles in the Development of Normal Prostate, Benign Prostate Hyperplasia, and Prostate Cancer

    Science.gov (United States)

    Wen, Simeng; Chang, Hong-Chiang; Tian, Jing; Shang, Zhiqun; Niu, Yuanjie; Chang, Chawnshang

    2016-01-01

    The prostate is an androgen-sensitive organ that needs proper androgen/androgen receptor (AR) signals for normal development. The progression of prostate diseases, including benign prostate hyperplasia (BPH) and prostate cancer (PCa), also needs proper androgen/AR signals. Tissue recombination studies report that stromal, but not epithelial, AR plays more critical roles via the mesenchymal-epithelial interactions to influence the early process of prostate development. However, in BPH and PCa, much more attention has been focused on epithelial AR roles. However, accumulating evidence indicates that stromal AR is also irreplaceable and plays critical roles in prostate disease progression. Herein, we summarize the roles of stromal AR in the development of normal prostate, BPH, and PCa, with evidence from the recent results of in vitro cell line studies, tissue recombination experiments, and AR knockout animal models. Current evidence suggests that stromal AR may play positive roles to promote BPH and PCa progression, and targeting stromal AR selectively with AR degradation enhancer, ASC-J9, may allow development of better therapies with fewer adverse effects to battle BPH and PCa. PMID:25432062

  16. Immunohistochemical expression of CD44s in human neuroblastic tumors: Moroccan experience and highlights on current data.

    Science.gov (United States)

    Tabyaoui, Imane; Tahiri-Jouti, Nadia; Serhier, Zineb; Bennani-Othmani, Mohamed; Sibai, Hicham; Itri, Mohamed; Benchekroun, Said; Zamiati, Soumaya

    2013-02-27

    Peripheral neuroblastic tumors (pNTs), including neuroblastoma (NB), ganglioneuroblastoma (GNB) and ganglioneuroma (GN), are extremely heterogeneous pediatric tumors responsible for 15 % of childhood cancer death. The aim of the study was to evaluate the expression of CD44s ('s': standard form) cell adhesion molecule by comparison with other specific prognostic markers. An immunohistochemical profile of 32 formalin-fixed paraffin-embedded pNTs tissues, diagnosed between January 2007 and December 2010, was carried out. Our results have demonstrated the association of CD44s negative pNTs cells to lack of differentiation and tumour progression. A significant association between absence of CD44s expression and metastasis in human pNTs has been reported. We also found that expression of CD44s defines subgroups of patients without MYCN amplification as evidenced by its association with low INSS stages, absence of metastasis and favorable Shimada histology. These findings support the thesis of the role of CD44s glycoprotein in the invasive growth potential of neoplastic cells and suggest that its expression could be taken into consideration in the therapeutic approaches targeting metastases. The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1034403150888863

  17. Exercise, physical activity and breast cancer: the role of tumor-associated macrophages.

    Science.gov (United States)

    Goh, Jorming; Kirk, Elizabeth A; Lee, Shu Xian; Ladiges, Warren C

    2012-01-01

    Regular exercise and physical activity provide many health benefits and are encouraged by medical professionals for the primary prevention of and adjuvant treatment of breast cancer Current consensus in the discipline of exercise oncology is that both regular physical activity and exercise training exert some protective effect against breast cancer risk, and may reduce morbidity in some advanced cases. While there is growing interest in the role of exercise and physical activity in breast cancer prevention, it is currently unclear how exercise may modulate tumor behavior. The tumor microenvironment is populated by stromal cells such as fibroblasts and adipocytes, as well as macrophages. Termed tumor-associated macrophages (TAMs), these immune cells are highly plastic and respond to different signals from the cancer microenvironment, causing them to either display tumor-promoting or tumor-suppressing phenotypes. Because of such plasticity, there has been considerable interest by immunologists to develop immunotherapies based on skewing the behavior of TAMs to become cancer-suppressive. Previous studies have indirectly shown the ability of exercise training to induce an anti-tumor effect of macrophages, although the studies did not address this in the tumor microenvironment. Nevertheless, this opens up the possibility that regular exercise training may exert a protective innate immune effect against breast cancer, potentially by inducing a cancer-suppressing phenotype of TAMs. This review will describe potential mechanisms through which exercise may modulate the behavior of TAMs.

  18. Activation of TRPA1 Channel by Antibacterial Agent Triclosan Induces VEGF Secretion in Human Prostate Cancer Stromal Cells.

    Science.gov (United States)

    Derouiche, Sandra; Mariot, Pascal; Warnier, Marine; Vancauwenberghe, Eric; Bidaux, Gabriel; Gosset, Pierre; Mauroy, Brigitte; Bonnal, Jean-Louis; Slomianny, Christian; Delcourt, Philippe; Dewailly, Etienne; Prevarskaya, Natalia; Roudbaraki, Morad

    2017-03-01

    Accruing evidence indicates that exposure to environmental compounds may adversely affect human health and promote carcinogenesis. Triclosan (TCS), an antimicrobial agent widely used as a preservative in personal care products, has been shown to act as an endocrine disruptor in hormone-dependent tissues. Here, we demonstrate a new molecular mechanism by which TCS stimulates the secretion by human prostate cancer stromal cells of vascular endothelial growth factor (VEGF), a factor known to promote tumor growth. This mechanism involves an increase in intracellular calcium levels due to the direct activation of a membrane ion channel. Using calcium imaging and electrophysiology techniques, we show for the first time that environmentally relevant concentrations of TCS activate a cation channel of the TRP family, TRPA1 (Transient Receptor Potential Ankirin 1), in primary cultured human prostate cancer stromal cells. The TCS-induced TRPA1 activation increased basal calcium in stromal cells and stimulated the secretion of VEGF and epithelial cells proliferation. Interestingly, immunofluorescence labeling performed on formalin-fixed paraffin-embedded prostate tissues showed an exclusive expression of the TRPA1 channel in prostate cancer stromal cells. Our data demonstrate an impact of the environmental factor TCS on the tumor microenvironment interactions, by activating a tumor stroma-specific TRPA1 ion channel. Cancer Prev Res; 10(3); 177-87. ©2017 AACR . ©2017 American Association for Cancer Research.

  19. Cycling hypoxia: A key feature of the tumor microenvironment.

    Science.gov (United States)

    Michiels, Carine; Tellier, Céline; Feron, Olivier

    2016-08-01

    A compelling body of evidence indicates that most human solid tumors contain hypoxic areas. Hypoxia is the consequence not only of the chaotic proliferation of cancer cells that places them at distance from the nearest capillary but also of the abnormal structure of the new vasculature network resulting in transient blood flow. Hence two types of hypoxia are observed in tumors: chronic and cycling (intermittent) hypoxia. Most of the current work aims at understanding the role of chronic hypoxia in tumor growth, response to treatment and metastasis. Only recently, cycling hypoxia, with spatial and temporal fluctuations in oxygen levels, has emerged as another key feature of the tumor environment that triggers different responses in comparison to chronic hypoxia. Either type of hypoxia is associated with distinct effects not only in cancer cells but also in stromal cells. In particular, cycling hypoxia has been demonstrated to favor, to a higher extent than chronic hypoxia, angiogenesis, resistance to anti-cancer treatments, intratumoral inflammation and tumor metastasis. These review details these effects as well as the signaling pathway it triggers to switch on specific transcriptomic programs. Understanding the signaling pathways through which cycling hypoxia induces these processes that support the development of an aggressive cancer could convey to the emergence of promising new cancer treatments. Copyright © 2016 Elsevier B.V. All rights reserved.

  20. Endometrial Stromal Sarcoma Arising in Colorectal Endometriosis: A Case Report and Review of the Literature

    Directory of Open Access Journals (Sweden)

    Qiao Wang

    2015-01-01

    Full Text Available Extrauterine endometrial stromal sarcoma (ESS arising in endometriosis is extremely rare, particularly in the colorectum. It should always be included in the differential diagnosis of primary tumors originating from gastrointestinal tract in females, given that preoperative endoscopical biopsy may reveal no specific changes. We reported a case of ESS arising in colorectal endometriosis and reviewed the previous 7 cases reported in the English literature. Our patient, who was unavailable for tumor resection and refused further adjuvant therapy, played a role in representing the natural history of low-grade extragenital ESS. This case was the only death from ESS arising in colorectal endometriosis.

  1. Parenchyma-stromal interactions induce fibrosis by secreting CCN2 and promote osteoclastogenesis by stimulating RANKL and CD68 through activated TGF-β/BMP4 in ameloblastoma.

    Science.gov (United States)

    Takebe, Yuichiro; Tsujigiwa, Hidetsugu; Katase, Naoki; Siar, Chong Huat; Takabatake, Kiyofumi; Fujii, Masae; Tamamura, Ryo; Nakano, Keisuke; Nagatsuka, Hitoshi

    2017-01-01

    Tumor parenchyma-stromal interactions affect the properties of tumors and their dynamics. Our group previously showed that secreted frizzled related protein (sFRP)-2 impairs bone formation and promotes bone invasion in ameloblastoma. However, the effects of the secreted growth factors CCN2, TGF-β, and BMP4 on stromal tissues in ameloblastoma remain unclear. Thirty-five paraffin-embedded ameloblastoma cases, ameloblastoma-derived cell lines (AM-1), and primary cultures of ameloblastoma stromal fibroblasts (ASF) were used. Immunohistochemistry, MTT assay, Western blotting, and RT-PCR were performed on these samples. Parenchyma-stromal CCN2 overexpression correlated significantly with fibrous-type stroma, but not with myxoid-type stroma, suggesting a role of CCN2 in fibrosis (P ameloblastoma with fibrous-type stroma. These data suggest that stromal properties influence bone resorption-related activities and growth rates, respectively. These results suggest that the effects of secreted growth factors are governed by ameloblastoma parenchyma-stromal interactions. CCN2 promotes fibrogenesis independent of TGF-β signaling. Absence of CCN2 expression is associated with a phenotypic switch to a myxoid-type microenvironment that is conducive for TGF-β/BMP4 signaling to promote osteoclastogenesis. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  2. Interleukin-6 mediates epithelial-stromal interactions and promotes gastric tumorigenesis.

    Directory of Open Access Journals (Sweden)

    Hiroto Kinoshita

    Full Text Available Interleukin-6 (IL-6 is a pleiotropic cytokine that affects various functions, including tumor development. Although the importance of IL-6 in gastric cancer has been documented in experimental and clinical studies, the mechanism by which IL-6 promotes gastric cancer remains unclear. In this study, we investigated the role of IL-6 in the epithelial-stromal interaction in gastric tumorigenesis. Immunohistochemical analysis of human gastritis, gastric adenoma, and gastric cancer tissues revealed that IL-6 was frequently detected in the stroma. IL-6-positive cells in the stroma showed positive staining for the fibroblast marker α-smooth muscle actin, suggesting that stromal fibroblasts produce IL-6. We compared IL-6 knockout (IL-6(-/- mice with wild-type (WT mice in a model of gastric tumorigenesis induced by the chemical carcinogen N-methyl-N-nitrosourea. The stromal fibroblasts expressed IL-6 in tumors from WT mice. Gastric tumorigenesis was attenuated in IL-6(-/- mice, compared with WT mice. Impaired tumor development in IL-6(-/- mice was correlated with the decreased activation of STAT3, a factor associated with gastric cancer cell proliferation. In vitro, when gastric cancer cell line was co-cultured with primary human gastric fibroblast, STAT3-related genes including COX-2 and iNOS were induced in gastric cancer cells and this response was attenuated with neutralizing anti-IL-6 receptor antibody. IL-6 production from fibroblasts was increased when fibroblasts were cultured in the presence of gastric cancer cell-conditioned media. IL-6 production from fibroblasts was suppressed by an interleukin-1 (IL-1 receptor antagonist and siRNA inhibition of IL-1α in the fibroblasts. IL-1α mRNA and protein were increased in fibroblast lysate, suggesting that cell-associated IL-1α in fibroblasts may be involved. Our results suggest the importance of IL-6 mediated stromal-epithelial cell interaction in gastric tumorigenesis.

  3. Primary Carcinosarcoma of Ovary an Unusual Tumor Case Report ...

    African Journals Online (AJOL)

    Primary Carcinosarcoma of Ovary an Unusual Tumor Case Report with Review of Literature. ... There is variable admixture of both malignant epithelial and stromal component seen in this tumor. We report a ... The epithelial and sarcomatous components showed immunohistochemical positivity for their respective markers.

  4. Stromal CD8+ T-cell Density—A Promising Supplement to TNM Staging in Non-Small Cell Lung Cancer

    DEFF Research Database (Denmark)

    Donnem, Tom; Hald, Sigurd M; Paulsen, Erna-Elise

    2015-01-01

    immunology is recognized as highly important. We have previously evaluated the prognostic impact of several immunological markers in NSCLC, yielding the density of stromal CD8(+) tumor-infiltrating lymphocytes (TIL) as the most promising candidate. Hence, we validate the impact of stromal CD8(+) TIL density...... as an immunoscore in NSCLC. EXPERIMENTAL DESIGN: The prognostic impact of stromal CD8(+) TILs was evaluated in four different cohorts from Norway and Denmark consisting of 797 stage I-IIIA NSCLC patients. The Tromso cohort (n = 155) was used as training set, and the results were further validated in the cohorts...... from Bodo (n = 169), Oslo (n = 295), and Denmark (n = 178). Tissue microarrays and clinical routine CD8 staining were used for all cohorts. RESULTS: Stromal CD8(+) TIL density was an independent prognostic factor in the total material (n = 797) regardless of the endpoint: disease-free survival (P

  5. The Bone Marrow-Derived Stromal Cells

    DEFF Research Database (Denmark)

    Tencerova, Michaela; Kassem, Moustapha

    2016-01-01

    diseases. BM stromal cells (also known as skeletal or mesenchymal stem cells) [bone marrow stromal stem cell (BMSC)] are multipotent stem cells located within BM stroma and give rise to osteoblasts and adipocytes. However, cellular and molecular mechanisms of BMSC lineage commitment to adipocytic lineage...... and regulation of BM adipocyte formation are not fully understood. In this review, we will discuss recent findings pertaining to identification and characterization of adipocyte progenitor cells in BM and the regulation of differentiation into mature adipocytes. We have also emphasized the clinical relevance...

  6. Mesenchymal Stromal Cell Dependent Regression of Pulmonary Metastasis from Ewing's

    Directory of Open Access Journals (Sweden)

    Andrea Anita Hayes-Jordan

    2014-05-01

    Full Text Available Introduction: Ewing’s sarcoma (ES is the second most common bone tumor in children. Survival has not improved over the last decade and once pulmonary metastatic disease is present, survival is dismal. Mesenchymal stromal cell (MSC therapy has shown potential benefit for Kaposi's sarcoma; however, the role of progenitor cell therapies for cancer remains controversial. MSC treatment of ES or pulmonary metastatic disease has not been demonstrated. We have developed an orthotopic xenograft model of ES in which animals develop spontaneous pulmonary metastases. Within this model, we demonstrate the use of MSCs to target ES lung metastasis. Materials and MethodsHuman ES cells were transfected with luciferase and injected into the rib of nude mice. Development of pulmonary metastases was confirmed by imaging. After flow cytometry based characterization, MSC’s were injected into the tail vein of nude mice with established local ES tumor or pulmonary metastasis. Mice were treated with intravenous MSCs weekly followed by bioluminescent imaging.ResultsThe intravenous injection of MSCs in an ES model decreases the volume of pulmonary metastatic lesions; however, no effect on primary chest wall tumor size is observed. Thus verifying the MSC preferential homing to the lung. MSCs are found to ‘home to’ the pulmonary parenchyma and remain engrafted up to 5 days after delivery. DiscussionMSC treatment of ES slows growth of pulmonary metastasis. MSC’s have more affinity for pulmonary metastasis and can effect a greater decrease in tumor growth in the lungs compared to the primary tumor site

  7. Stromal PDGFR-β Expression is Associated with Postoperative Survival of Non-Small Cell Lung Cancer Patients Receiving Preoperative Chemo- or Chemoradiotherapy Followed by Surgery.

    Science.gov (United States)

    Kanzaki, Ryu; Ose, Naoko; Kawamura, Tomohiro; Funaki, Soichiro; Shintani, Yasushi; Minami, Masato; Takakura, Nobuyuki; Okumura, Meinoshin

    2018-03-06

    PDGFR-β is used as a stromal biomarker and is functional in mesenchymal cells of the tumor microenvironment. The significance of stromal PDGFR-β expression in non-small cell lung cancer (NSCLC) in patients undergoing preoperative chemo- or chemoradiotherapy had not been determined. Patients with NSCLC undergoing preoperative chemo- or chemoradiotherapy between 1996 and 2014 were assessed for expression of stromal PDGFR-β by immunohistochemistry using resected specimens. Relationships between stromal PDGFR-β expression and survival after operation were analyzed. Forty-three patients who underwent surgery without preoperative treatment in 2005 were also analyzed as a chemo-naïve control group. The mean age of the 92 patients was 60.2 years. Seventy-eight (85%) were male, and 14 (15%) were female. Fifty-four patients (59%) underwent preoperative chemoradiotherapy, and 38 patients (41%) underwent preoperative chemotherapy. Regimens for preoperative chemotherapy were cisplatin (CDDP) based in 48 patients (52%) and carboplatin (CBDCA) based in 43 (42%). While stromal cells expressed PDGFR-β in 21 chemo-naïve patients (49%), stromal cells expressed PDGFR-β in 65 patients who underwent preoperative therapy (p = 0.02). The 5-year disease-free survival rate (DFS) of the PDGFR-β-positive group was significantly worse than that of the negative group (27 vs. 48%, p = 0.04). The 5-year disease-specific survival rate (DSS) in the stromal PDGFR-β-positive group was also significantly worse than in the negative group (43 vs. 70%, p = 0.01). On the other hand, stromal PDGFR-β expression did not influence survival in chemo-naïve patients. Stromal PDGFR-β expression is negatively associated with DFS and DSS in patients with NSCLC undergoing preoperative chemo- or chemoradiotherapy.

  8. Accelerated Tumor Cell Death by Anglogenic Modifiers

    Science.gov (United States)

    2005-08-01

    morphologic "desmoplastic" stromal response tumor may be responsible for carcinogenesis in to tumor epithelium often occurs around either primary primary ...differentiation of enamel tooth epithelium. Based 2001; Hsieh et al., 2002). This concept of bone targeting upon this and other published data, we proposed that...synergism between squalamine and VEGF (or castration), and assessment of the biochemical and morphologic changes of the prostatic tissues in vivo: This task

  9. Breast cancer and the stromal factor: The "prometastatic healing process" hypothesis

    Directory of Open Access Journals (Sweden)

    Mario Wernicke

    2011-02-01

    Full Text Available The correlation between axillary status and several histological features of breast carcinomas has been well established, however stromal changes have rarely been analyzed. Detailed clinicopathological review of 1803 patients with infiltrating breast carcinoma was performed. Stromal myxoid changes (SMC, size (T2-T3: > 2 cm, T1c: 1-2 cm, T1 a-b: < 1cm, fibrotic focus, age, lymphovascular embolizations, tumor infiltrating lymphocytes (TIL, multifocality, histological grade (G, estrogen receptors (ER, progesterone receptors (PR and HER2 were semi-quantitated in two or three grades and correlated to axillary status. SMC3 followed by T2-T3, G3, fibrotic focus, T1c, embolizations, SMC2, TIL2, G2 and multifocality were strongly associated with positive axillary nodes; an inverse association was found with ER+++ and PR+++. Our findings support a critical role of the peritumoral stroma in the development of metastases. These stromal alterations should be remarked in routine pathology reports as they can be easily assessed and provide important information about tumor biology and aggressiveness. They could also become, in a future, the target of novel therapeutics.

  10. Uterine sarcoma – current perspectives

    Science.gov (United States)

    Benson, Charlotte; Miah, Aisha B

    2017-01-01

    Uterine sarcomas comprise a group of rare tumors with differing tumor biology, natural history and response to treatment. Diagnosis is often made following surgery for presumed benign disease. Currently, preoperative imaging does not reliably distinguish between benign leiomyomas and other malignant pathology. Uterine leiomyosarcoma is the most common sarcoma, but other subtypes include endometrial stromal sarcoma (low grade and high grade), undifferentiated uterine sarcoma and adenosarcoma. Clinical trials have shown no definite survival benefit of adjuvant radiotherapy or chemotherapy and have been hampered by the rarity and heterogeneity of these disease types. There is a role of adjuvant treatment in carefully selected cases following multidisciplinary discussion at sarcoma reference centers. In patients with metastatic disease, systemic chemotherapy can then be considered. There is activity of a number of agents, including doxorubicin, trabectedin, gemcitabine-based chemotherapy, eribulin and pazopanib. Patients should be considered for clinical trial entry where possible. Close international collaboration is important to allow progress in this group of diseases. PMID:28919822

  11. Determinación inmunohistoquímica y utilidad pronóstica del receptor del factor de crecimiento epidérmico en los tumores estromales gastrointestinales Immnunohistochemical expression of epidermal growth factor and its prognostic value for gastrointestinal stromal tumors

    Directory of Open Access Journals (Sweden)

    D. Padilla

    2008-12-01

    Full Text Available Introducción: el receptor del factor de crecimiento epidérmico, EGFR(HER-1, es un receptor de tirosina quinasas cuya activación permite un aumento de la proliferación celular, angiogénesis, proceso metastásico y disminución de la apoptosis celular. Nuestro objetivo es conocer el valor pronóstico de la inmunotinción de EGFR en tumores estromales gastrointestinales (GIST. Pacientes y método: estudio retrospectivo que incluye todos los GIST intervenidos quirúrgicamente entre 1995-2007 en el Servicio de Cirugía General y del Aparato Digestivo del Hospital General de Ciudad Real. Variables clínicas: edad, sexo, clínica, mortalidad, recidiva. Variables patológicas: a macroscópicas: localización, diámetro; b microscópicas: necrosis tumoral, índice mitótico, tipo celular; y c inmunohistoquímicas: vimentina (V9, Dako A/s; actina del músculo liso (HHF-35, Biogenex; CD34 (QBEND/10; S100 (Policlonal Dako A/S; CD117 (c-kit Rabbit, antihuman polyclonal antibody, 1:600; PDGFR-alfa (Rabbit polyclonal antibody, 1:50, Sta. Cruz Biotechnology. Variables moleculares pronósticas: P-53, PAb240 (DakoCytomation, 1:75, Ki-67, clona MIB1 (Dako, 1:120 y EGFR pharmDx™ Dako Autostainer (Dako, Dinamarca. Criterios de malignidad: criterios de Fletcher. Resultados: entre 1995 y 2007, 35 GIST, fueron intervenidos quirúrgicamente en nuestro Servicio. Edad media: 61,11 ± 11,02, siendo mujeres en el 62,9% de los casos. Debutaron con hemorragia digestiva en un 40%. La mediana de seguimiento fue de 28 meses (3-133. La mortalidad fue de 54,3%, con recidiva del 40%. Variables morfológicas: la localización más frecuente fue gástrica, 51,4% (18. Existió necrosis tumoral en un 57,1%, 20. El patrón celular fue fusocelular en un 57,1%, y epitelioide en un 14,3%. El diámetro máximo fue de 9,58 ± 6,29. El índice mitótico por 50 campos de gran aumento fue de 13,44 ± 16,08. En un 51,45%, 18, fueron neoplasias de alto riesgo. Valores inmunohistoqu

  12. Gastrointestinal stromal tumour presenting as gastroduodenal intussusception.

    LENUS (Irish Health Repository)

    Wilson, Mark H

    2012-08-01

    Gastroduodenal intussusception secondary to gastrointestinal stromal tumour is a very rare cause for intestinal obstruction. The diagnosis of this condition can be challenging, as symptoms are often non-specific and intermittent. This article reports a case where the diagnosis was made preoperatively with abdominal imaging and was treated by a combination of endoscopic reduction and laparoscopic resection.

  13. Cryopreservation and revival of mesenchymal stromal cells

    DEFF Research Database (Denmark)

    Haack-Sørensen, Mandana; Kastrup, Jens

    2011-01-01

    initiated. As there has been a precedent for the use of bone marrow stem cells in the treatment of hematological malignancies and ischemic heart diseases through randomized clinical safety and efficacy trials, the development of new therapies based on culture-expanded human mesenchymal stromal cells (MSCs...

  14. Targeting the tumor microenvironment for cancer therapy.

    Science.gov (United States)

    Sounni, Nor Eddine; Noel, Agnès

    2013-01-01

    With the emergence of the tumor microenvironment as an essential ingredient of cancer malignancy, therapies targeting the host compartment of tumors have begun to be designed and applied in the clinic. The malignant features of cancer cells cannot be manifested without an important interplay between cancer cells and their local environment. The tumor infiltrate composed of immune cells, angiogenic vascular cells, lymphatic endothelial cells, and cancer-associated fibroblastic cells contributes actively to cancer progression. The ability to change these surroundings is an important property by which tumor cells are able to acquire some of the hallmark functions necessary for tumor growth and metastatic dissemination. Thus in the clinical setting the targeting of the tumor microenvironment to encapsulate or destroy cancer cells in their local environment has become mandatory. The variety of stromal cells, the complexity of the molecular components of the tumor stroma, and the similarity with normal tissue present huge challenges for therapies targeting the tumor microenvironment. These issues and their interplay are addressed in this review. After a decade of intensive clinical trials targeting cellular components of the tumor microenvironment, more recent investigations have shed light on the important role in cancer progression played by the noncellular stromal compartment composed of the extracellular matrix. A better understanding of how the tumor environment affects cancer progression should provide new targets for the isolation and destruction of cancer cells via interference with the complex crosstalk established between cancer cells, host cells, and their surrounding extracellular matrix. © 2012 American Association for Clinical Chemistry

  15. Corneal stromal dystrophies: a clinical pathologic study

    Directory of Open Access Journals (Sweden)

    Elvira Barbosa Abreu

    2012-12-01

    Full Text Available INTRODUCTION: Corneal dystrophy is defined as bilateral and symmetric primary corneal disease, without previous associated ocular inflammation. Corneal dystrophies are classified according to the involved corneal layer in superficial, stromal, and posterior dystrophy. Incidence of each dystrophy varies according to the geographic region studied. PURPOSE: To evaluate the prevalence of stromal corneal dystrophies among corneal buttons specimens obtained by penetrating keratoplasty (PK in an ocular pathology laboratory and to correlate the diagnosis with patient age and gender. METHODS: Corneal button cases of penetrating keratoplasty from January-1996 to May-2009 were retrieved from the archives of The Henry C. Witelson Ophthalmic Pathology Laboratory and Registry, Montreal, Canada. The cases with histopathological diagnosis of stromal corneal dystrophies were stained with special stains (Peroxid acid Schiff, Masson trichrome, Congo red analyzed under polarized light, and alcian blue for classification and correlated with epidemiological information (age at time of PK and gender from patients' file. RESULTS: 1,300 corneal buttons cases with clinical diagnose of corneal dystrophy were retrieved. Stromal corneal dystrophy was found in 40 (3.1% cases. Lattice corneal dystrophy was the most prevalent with 26 cases (65%. Nineteen were female (73.07% and the PK was performed at average age of 59.3 years old. Combined corneal dystrophy was found in 8 (20% cases, 5 (62.5% of them were female and the average age of the penetrating keratoplasty was 54.8 years old. Granular corneal dystrophy was represented by 5 (12.5% cases, and 2 (40% of them were female. Penetrating keratoplasty was performed at average age of 39.5 years old in granular corneal dystrophy cases. Macular corneal dystrophy was present in only 1 (2.5% case, in a 36 years old female. CONCLUSION: Systematic histopathological approach and evaluation, including special stains in all stromal

  16. Stromal Gene Expression is Predictive for Metastatic Primary Prostate Cancer.

    Science.gov (United States)

    Mo, Fan; Lin, Dong; Takhar, Mandeep; Ramnarine, Varune Rohan; Dong, Xin; Bell, Robert H; Volik, Stanislav V; Wang, Kendric; Xue, Hui; Wang, Yuwei; Haegert, Anne; Anderson, Shawn; Brahmbhatt, Sonal; Erho, Nicholas; Wang, Xinya; Gout, Peter W; Morris, James; Karnes, R Jeffrey; Den, Robert B; Klein, Eric A; Schaeffer, Edward M; Ross, Ashley; Ren, Shancheng; Sahinalp, S Cenk; Li, Yingrui; Xu, Xun; Wang, Jun; Wang, Jian; Gleave, Martin E; Davicioni, Elai; Sun, Yinghao; Wang, Yuzhuo; Collins, Colin C

    2018-04-01

    Clinical grading systems using clinical features alongside nomograms lack precision in guiding treatment decisions in prostate cancer (PCa). There is a critical need for identification of biomarkers that can more accurately stratify patients with primary PCa. To identify a robust prognostic signature to better distinguish indolent from aggressive prostate cancer (PCa). To develop the signature, whole-genome and whole-transcriptome sequencing was conducted on five PCa patient-derived xenograft (PDX) models collected from independent foci of a single primary tumor and exhibiting variable metastatic phenotypes. Multiple independent clinical cohorts including an intermediate-risk cohort were used to validate the biomarkers. The outcome measurement defining aggressive PCa was metastasis following radical prostatectomy. A generalized linear model with lasso regularization was used to build a 93-gene stroma-derived metastasis signature (SDMS). The SDMS association with metastasis was assessed using a Wilcoxon rank-sum test. Performance was evaluated using the area under the curve (AUC) for the receiver operating characteristic, and Kaplan-Meier curves. Univariable and multivariable regression models were used to compare the SDMS alongside clinicopathological variables and reported signatures. AUC was assessed to determine if SDMS is additive or synergistic to previously reported signatures. A close association between stromal gene expression and metastatic phenotype was observed. Accordingly, the SDMS was modeled and validated in multiple independent clinical cohorts. Patients with higher SDMS scores were found to have worse prognosis. Furthermore, SDMS was an independent prognostic factor, can stratify risk in intermediate-risk PCa, and can improve the performance of other previously reported signatures. Profiling of stromal gene expression led to development of an SDMS that was validated as independently prognostic for the metastatic potential of prostate tumors. Our

  17. The role of stromal cells in inflammatory bone loss.

    Science.gov (United States)

    Wehmeyer, C; Pap, T; Buckley, C D; Naylor, A J

    2017-07-01

    Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation, local and systemic bone loss and a lack of compensatory bone repair. Fibroblast-like synoviocytes (FLS) are the most abundant cells of the stroma and a key population in autoimmune diseases such as RA. An increasing body of evidence suggests that these cells play not only an important role in chronic inflammation and synovial hyperplasia, but also impact bone remodelling. Under inflammatory conditions FLS release inflammatory cytokines, regulate bone destruction and formation and communicate with immune cells to control bone homeostasis. Other stromal cells, such as osteoblasts and terminally differentiated osteoblasts, termed osteocytes, are also involved in the regulation of bone homeostasis and are dysregulated during inflammation. This review highlights our current understanding of how stromal cells influence the balance between bone formation and bone destruction. Increasing our understanding of these processes is critical to enable the development of novel therapeutic strategies with which to treat bone loss in RA. © 2017 British Society for Immunology.

  18. Regenerative Potential of Mesenchymal Stromal Cells: Age-Related Changes.

    Science.gov (United States)

    Bruna, Flavia; Contador, David; Conget, Paulette; Erranz, Benjamín; Sossa, Claudia L; Arango-Rodríguez, Martha L

    2016-01-01

    Preclinical and clinical studies have shown that a therapeutic effect results from mesenchymal stromal cells (MSCs) transplant. No systematic information is currently available regarding whether donor age modifies MSC regenerative potential on cutaneous wound healing. Here, we evaluate whether donor age influences this potential. Two different doses of bone marrow MSCs (BM-MSCs) from young, adult, or old mouse donors or two doses of their acellular derivatives mesenchymal stromal cells (acd-MSCs) were intradermally injected around wounds in the midline of C57BL/6 mice. Every two days, wound healing was macroscopically assessed (wound closure) and microscopically assessed (reepithelialization, dermal-epidermal junction, skin appendage regeneration, granulation tissue, leukocyte infiltration, and density dermal collagen fibers) after 12 days from MSC transplant. Significant differences in the wound closure kinetic, quality, and healing of skin regenerated were observed in lesions which received BM-MSCs from different ages or their acd-MSCs compared to lesions which received vehicle. Nevertheless, our data shows that adult's BM-MSCs or their acd-MSCs were the most efficient for recovery of most parameters analyzed. Our data suggest that MSC efficacy was negatively affected by donor age, where the treatment with adult's BM-MSCs or their acd-MSCs in cutaneous wound promotes a better tissue repair/regeneration. This is due to their paracrine factors secretion.

  19. Regenerative Potential of Mesenchymal Stromal Cells: Age-Related Changes

    Directory of Open Access Journals (Sweden)

    Flavia Bruna

    2016-01-01

    Full Text Available Preclinical and clinical studies have shown that a therapeutic effect results from mesenchymal stromal cells (MSCs transplant. No systematic information is currently available regarding whether donor age modifies MSC regenerative potential on cutaneous wound healing. Here, we evaluate whether donor age influences this potential. Two different doses of bone marrow MSCs (BM-MSCs from young, adult, or old mouse donors or two doses of their acellular derivatives mesenchymal stromal cells (acd-MSCs were intradermally injected around wounds in the midline of C57BL/6 mice. Every two days, wound healing was macroscopically assessed (wound closure and microscopically assessed (reepithelialization, dermal-epidermal junction, skin appendage regeneration, granulation tissue, leukocyte infiltration, and density dermal collagen fibers after 12 days from MSC transplant. Significant differences in the wound closure kinetic, quality, and healing of skin regenerated were observed in lesions which received BM-MSCs from different ages or their acd-MSCs compared to lesions which received vehicle. Nevertheless, our data shows that adult’s BM-MSCs or their acd-MSCs were the most efficient for recovery of most parameters analyzed. Our data suggest that MSC efficacy was negatively affected by donor age, where the treatment with adult’s BM-MSCs or their acd-MSCs in cutaneous wound promotes a better tissue repair/regeneration. This is due to their paracrine factors secretion.

  20. How to manage pseudoangiomatous stromal hyperplasia: our clinical experience

    Science.gov (United States)

    Kurt, Emine; Turanlı, Sevim; Markoç, Fatma; Berberoğlu, Uğur

    2017-11-13

    Background/aim: Pseudoangiomatous stromal hyperplasia (PASH) is a rare and benign mesenchymal proliferative breast lesion. Our aim is to review the clinical and radiological features of PASH and define a standard approach for its diagnosis and management. Materials and methods: Clinical records of 35 consecutive patients with PASH were retrospectively reviewed between 2009 and 2015. Patients with clinically or radiologically detected mass and patients who underwent biopsy for other indications and were diagnosed incidentally were included in the study. Results: There were 34 female patients and one male patient with gynecomastia. Twenty-three patients had palpable masses, and 16 of them were diagnosed as PASH with a median size of 3.1 cm. PASH did not show any specific features in radiological imaging. Core needle biopsy was performed for 3 patients before surgical excision; however, the lesions had not been diagnosed as PASH. In pathological examination, lesions associated with PASH showed nonproliferative changes in 14 patients, proliferative changes without atypia in 17, one phyllodes tumor, one in situ tumor, and one invasive cancer. Conclusion: Imaging findings of PASH are nonspecific. It is difficult to give a true prognostic diagnosis through pathological evaluation of big masses with core needle biopsy. We recommend surgical excision, especially for big lesions with suspicious features.

  1. Cytogenetic and molecular profile of endometrial stromal sarcoma.

    Science.gov (United States)

    Micci, Francesca; Gorunova, Ludmila; Agostini, Antonio; Johannessen, Lene E; Brunetti, Marta; Davidson, Ben; Heim, Sverre; Panagopoulos, Ioannis

    2016-11-01

    Recent cytogenetic and molecular investigations have improved our understanding of endometrial stromal tumors, including sarcomas (ESS), and helped redefine their classification into more pathogenetically meaningful categories. Because much more can be gained through such studies, we add information on another 22 ESS examined by karyotyping, PCR analysis, expression array analysis, and transcriptome sequencing. In spite of the known preference for certain pathogenetic pathways, we found considerable genetic heterogeneity in high-grade (HG) as well as in low-grade (LG) ESS. Not all HG tumors showed a YWHAE-NUTM chimeric transcript and as many as six LGESS showed no hitherto known ESS-related fusions. Among the transcripts identified by transcriptome sequencing and verified by Sanger sequencing, new variants of ZC3H7-BCOR and its reciprocal BCOR-ZC3H7 were identified as was involvement of the CREBBP and MLLT4 genes (both well known leukemia-related genes) in two new fusions. FISH analysis identified a known EPC1-PHF1 fusion which led to the identification of a new variant at the molecular level. The fact that around 70 genes were found differentially expressed, by microarray analysis, when comparing LGESS showing ESS-related fusions with LGESS without such transcripts, underscores the biochemical importance of the observed genetic heterogeneity and hints that new subgroups/entities in LGESS still remain undiscovered. © 2016 The Authors. Genes, Chromosomes & Cancer Published by Wiley Periodicals, Inc. © 2016 The Authors. Genes, Chromosomes & Cancer Published by Wiley Periodicals, Inc.

  2. Uterine Tumor Resembling Ovarian Sex Cord Tumor (UTROSCT) Commonly Exhibits Positivity With Sex Cord Markers FOXL2 and SF-1 but Lacks FOXL2 and DICER1 Mutations.

    Science.gov (United States)

    Croce, Sabrina; de Kock, Leanne; Boshari, Talia; Hostein, Isabelle; Velasco, Valerie; Foulkes, William D; McCluggage, W Glenn

    2016-07-01

    Uterine tumor resembling ovarian sex cord tumor (UTROSCT) is a rare neoplasm which morphologically and immunohistochemically exhibits overlap with an ovarian sex cord tumor. Although many of these neoplasms are positive with markers of ovarian sex cord-stromal tumors, staining is often limited and the pathogenesis of UTROSCT is unknown. To further explore the sex cord lineage of UTROSCT, we studied 19 of these neoplasms and examined the expression of 2 recently described markers of ovarian sex cord-stromal tumors, FOXL2, and steroidogenic factor-1. We also undertook FOXL2 and DICER1 mutation analysis in these cases; a somatic missense mutation in codon C134W (402C→G) of FOXL2 gene has been demonstrated in the vast majority (>95%) of ovarian adult granulosa cell tumors and somatic DICER1 mutations are found in approximately 60% of ovarian Sertoli-Leydig cell tumors. Ten of 19 cases (53%) exhibited nuclear immunoreactivity with FOXL2 and 11 of 19 (58%) exhibited nuclear staining with steroidogenic factor-1. Neither FOXL2 nor DICER1 mutations were identified in any case where there was sufficient tumor tissue for analysis (18 and 9 cases, respectively). Despite exhibiting an immunophenotype characteristic of a sex cord-stromal tumor, mutations in FOXL2 and DICER1, the 2 most common mutations hitherto reported in ovarian sex cord-stromal tumors, are not a feature of UTROSCT.

  3. Amide proton transfer imaging in clinics: Basic concepts and current and future use in brain tumors and stoke

    Energy Technology Data Exchange (ETDEWEB)

    Park, Ji Eun [Dept. of Radiology and Research Institute of Radiology, University of Ulsan College of Medicine, Asan Medical Center, Seoul (Korea, Republic of); Jahng, Geon Ho [Dept. of Radiology, Kyung Hee University Hospital at Gangdong, College of Medicine, Kyung Hee University, Seoul (Korea, Republic of); Jeong, Ha Kyu [Philips Korea, Seoul (Korea, Republic of)

    2016-12-15

    Amide proton transfer (APT) imaging is gaining attention as a relatively new in vivo molecular imaging technique that has higher sensitivity and spatial resolution than magnetic resonance spectroscopy imaging. APT imaging is a subset of the chemical exchange saturation transfer mechanism, which can offer unique image contrast by selectively saturating protons in target molecules that get exchanged with protons in bulk water. In this review, we describe the basic concepts of APT imaging, particularly with regard to the benefit in clinics from the current literature. Clinical applications of APT imaging are described from two perspectives: in the diagnosis and monitoring of the treatment response in brain glioma by reflecting endogenous mobile proteins and peptides, and in the potential for stroke imaging with respect to tissue acidity.

  4. Obesity Enhances the Conversion of Adipose-Derived Stromal/Stem Cells into Carcinoma-Associated Fibroblast Leading to Cancer Cell Proliferation and Progression to an Invasive Phenotype

    Science.gov (United States)

    Pei, Dorothy T.; Hurst, Christian G.; Gimble, Jeffrey M.; Burow, Matthew E.

    2017-01-01

    Obesity is associated with enhanced tumor growth and progression. Within the adipose tissue are adipose-derived stromal/stem cells (ASCs) that have been shown to convert into carcinoma-associated fibroblast (CAFs) in the presence of tumor-derived factors. However, the impact of obesity on the ASCs and on the conversion of ASCs into CAFs has not been demonstrated. In the current study, ASCs isolated from lean donors (BMI  30, obASCs). The contribution of tumor-derived factors on the conversion of ASCs to CAFs was investigated. Following exposure to cancer cells, obASCs expressed higher levels of CAF markers, including NG2, alpha-SMA, VEGF, FAP, and FSP, compared to lnASCs. To investigate the crosstalk between ASCs and breast cancer cells, MCF7 cells were serially cocultured with lnASCs or obASCs. After coculture with lnASCs and obASCs, MCF7 cells demonstrated enhanced proliferation and expressed an invasive phenotype morphologically, with more pronounced effects following exposure to obASCs. Long-term exposure to obASCs also enhanced the expression of protumorgenic factors. Together, these results suggest that obesity alters ASCs to favor their rapid conversion into CAFs, which in turn enhances the proliferative rate, the phenotype, and gene expression profile of breast cancer cells. PMID:29527228

  5. Pathogenesis and treatment of adult-type granulosa cell tumor of the ovary.

    Science.gov (United States)

    Färkkilä, Anniina; Haltia, Ulla-Maija; Tapper, Johanna; McConechy, Melissa K; Huntsman, David G; Heikinheimo, Markku

    2017-08-01

    Adult-type granulosa cell tumor is a clinically and molecularly unique subtype of ovarian cancer. These tumors originate from the sex cord stromal cells of the ovary and represent 3-5% of all ovarian cancers. The majority of adult-type granulosa cell tumors are diagnosed at an early stage with an indolent prognosis. Surgery is the cornerstone for the treatment of both primary and relapsed tumor, while chemotherapy is applied only for advanced or non-resectable cases. Tumor stage is the only factor consistently associated with prognosis. However, every third of the patients relapse, typically in 4-7 years from diagnosis, leading to death in 50% of these patients. Anti-Müllerian Hormone and inhibin B are currently the most accurate circulating biomarkers. Adult-type granulosa cell tumors are molecularly characterized by a pathognomonic somatic missense point mutation 402C->G (C134W) in the transcription factor FOXL2. The FOXL2 402C->G mutation leads to increased proliferation and survival of granulosa cells, and promotes hormonal changes. Histological diagnosis of adult-type granulosa cell tumor is challenging, therefore testing for the FOXL2 mutation is crucial for differential diagnosis. Large international collaborations utilizing molecularly defined cohorts are essential to improve and validate new treatment strategies for patients with high-risk or relapsed adult-type granulosa cell tumor. Key Messages: Adult-type granulosa cell tumor is a unique ovarian cancer with an indolent, albeit unpredictable disease course. Adult-type granulosa cell tumors harbor a pathognomonic somatic missense mutation in transcription factor FOXL2. The key challenges in the treatment of patients with adult-type granulosa cell tumor lie in the identification and management of patients with high-risk or relapsed disease.

  6. Construction of a human corneal stromal equivalent with non-transfected human corneal stromal cells and acellular porcine corneal stromata.

    Science.gov (United States)

    Diao, Jin-Mei; Pang, Xin; Qiu, Yue; Miao, Ying; Yu, Miao-Miao; Fan, Ting-Jun

    2015-03-01

    A tissue-engineered human corneal stroma (TE-HCS) has been developed as a promising equivalent to the native corneal stroma for replacement