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Sample records for gastrointestinal stromal tumors

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

    MedlinePlus

    ... Stromal Tumor (GIST) About Gastrointestinal Stromal Tumor What’s New in Gastrointestinal Stromal Tumor Research and Treatment? There ... the Key Statistics About Gastrointestinal Stromal Tumors? What’s New in Gastrointestinal Stromal Tumor Research and Treatment? More ...

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

    MedlinePlus

    ... Gastrointestinal Stromal Tumors Be Prevented? Gastrointestinal Stromal Tumor (GIST) Causes, Risk Factors, and Prevention What Are the ... few known risk factors for gastrointestinal stromal tumors (GISTs). Being older These tumors can occur in people ...

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

    MedlinePlus

    ... About Gastrointestinal Stromal Tumor What Are the Key Statistics About Gastrointestinal Stromal Tumors? Gastrointestinal stromal tumors (GISTs) ... They are slightly more common in men. Survival statistics for GIST are discussed in “ Survival rates for ...

  4. Ghrelin and gastrointestinal stromal tumors

    PubMed Central

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

    2017-01-01

    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. PMID:28348480

  5. Ghrelin and gastrointestinal stromal tumors.

    PubMed

    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.

  6. What Happens After Treatment for Gastrointestinal Stromal Tumor?

    MedlinePlus

    ... Tumor Is No Longer Working Gastrointestinal Stromal Tumor (GIST) After Treatment What Happens After Treatment for Gastrointestinal ... For some people with a gastrointestinal stromal tumor (GIST), treatment may remove or destroy the cancer. Completing ...

  7. Gastrointestinal stromal tumors: the histology report.

    PubMed

    Dei Tos, Angelo P; Laurino, Licia; Bearzi, Italo; Messerini, Luca; Farinati, Fabio

    2011-03-01

    Gastrointestinal stromal tumors (GISTs) represent a mesenchymal neoplasm occurring primarily in the gastrointestinal tract, and showing differentiation toward the interstitial cell of Cajal. Its incidence is approximately 15 case/100,000/year. Stomach and small bowel are the most frequently affected anatomic sites. GIST represents a morphological, immunophenotypical and molecular distinct entity, the recognition of which has profound therapeutic implications. In fact, they have shown an exquisite sensitivity to treatment with the tyrosine kinase inhibitor imatinib. Diagnosis relies upon morphology along with immunodetection of KIT and/or DOG1. When dealing with KIT negative cases, molecular analysis of KIT/PDGFRA genes may help in confirming diagnosis. Molecular evaluation of both genes are in any case recommended as mutational status provides key predictive information. Pathologists also play a key role in providing an estimation of the risk of biological aggressiveness, which is currently based on anatomic location of the tumor, size, and mitotic activity.

  8. Update on Gastrointestinal Stromal Tumors for Radiologists

    PubMed Central

    Baheti, Akshay D.; Tirumani, Harika; O'Neill, Ailbhe; Jagannathan, Jyothi P.

    2017-01-01

    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. PMID:28096720

  9. Giant gastrointestinal stromal tumor of the stomach.

    PubMed

    Ionescu, Sever; Barbu, Emil; Ionescu, Călin; Costache, Adrian; Bălăşoiu, Maria

    2015-01-01

    Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal malignancies of the digestive tract. Gastric localization is the most frequent. The aim of this study is to evaluate the importance of immunohistochemical factors (CD117, CD34, α-SMA, vimentin, p53, Ki67) in diagnostic and size tumor and mitotic activity as prognostic factors for these tumors. We present the case of a 66-year-old male patient with a giant gastric GIST. Like in the vast majority, the symptomatology in this patient has long been faint, despite the large tumor size, and when it became manifest, it was nonspecific. Imagery wise, the computer tomography (CT) scan was the most efficient, showing the origin of the tumor from the greater curvature of the stomach, its dimensions, as well as the relations with the other abdominal viscera. Surgery in this patient was en-bloc, according to the principles of GIST. The histological aspect is characterized by a proliferation of spindle cells positive for CD117 and CD34. Despite complete microscopic resection, the size of the tumor (25×20×27 cm) and the mitotic activity (21÷5 mm2) remains important relapse factor.

  10. Gastrointestinal stromal tumors (GISTs) and second malignancies

    PubMed Central

    Rodriquenz, Maria Grazia; Rossi, Sabrina; Ricci, Riccardo; Martini, Maurizio; Larocca, Mario; Dipasquale, Angelo; Quirino, Michela; Schinzari, Giovanni; Basso, Michele; D’Argento, Ettore; Strippoli, Antonia; Barone, Carlo; Cassano, Alessandra

    2016-01-01

    Abstract Several evidences showed that patients with gastrointestinal stromal tumors (GISTs) develop additional malignancies. However, thorough incidence of second tumors remains uncertain as the possibility of a common molecular pathogenesis. A retrospective series of 128 patients with histologically proven GIST treated at our institution was evaluated. Molecular analysis of KIT and PDGFR-α genes was performed in all patients. Following the involvement of KRAS mutation in many tumors’ pathogenesis, analysis of KRAS was performed in patients with also second neoplasms. Forty-six out of 128 GIST patients (35.9%) had a second neoplasm. Most second tumors (52%) raised from gastrointestinal tract and 19.6% from genitourinary tract. Benign neoplasms were also included (21.7%). Molecular analysis was available for 29/46 patients with a second tumor: wild-type GISTs (n. 5), exon 11 (n. 16), exon 13 (n. 1), exon 9 (n. 1) KIT mutations, exon 14 PDGFR-α mutation (n. 2) and exon 18 PDGFR-α mutation (n. 4). KIT exon 11 mutations were more frequent between patients who developed a second tumor (P = 0.0003). Mutational analysis of KRAS showed a wild-type sequence in all cases. In metachronous cases, the median time interval between GIST and second tumor was 21.5 months. The high frequency of second tumors suggests that an unknown common molecular mechanism might play a role, but it is not likely that KRAS is involved in this common pathogenesis. The short interval between GIST diagnosis and the onset of second neoplasms asks for a careful follow-up, particularly in the first 3 years after diagnosis. PMID:27661019

  11. Intestinal gastrointestinal stromal tumor in a cat

    PubMed Central

    SUWA, Akihisa; SHIMODA, Tetsuya

    2017-01-01

    A 12-year-old, 3.6-kg, spayed female domestic shorthaired cat had a 2-month history of anorexia and weight loss. Abdominal ultrasonography and computed tomography revealed an exophytic mass originating from the jejunum with very poor central and poor peripheral contrast enhancement. On day 14, surgical resection of the jejunum and mass with 5-cm margins and an end-to-end anastomosis were performed. Histopathological examination revealed the mass was a transmural, invasive cancer showing exophytic growth and originating from the small intestinal muscle layer. Immunohistochemical analysis of tumor cells revealed diffuse positivity for KIT protein and negativity for desmin and S-100. The mass was diagnosed as a gastrointestinal stromal tumor (GIST). Ultrasonographic findings indicated the tumor probably metastasized to the liver and omentum, as seen in humans and dogs. The owner rejected further treatment at the last visit on day 192. To our knowledge, this is the first report of intestinal tumor and metastasis in feline GIST and its imaging features. PMID:28163271

  12. LAPAROSCOPIC RESECTION OF GASTROINTESTINAL STROMAL TUMORS (GIST)

    PubMed Central

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

    2016-01-01

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

  13. Meckel Diverticulum Harboring a Rare Gastrointestinal Stromal Tumor

    PubMed Central

    Berry, Andrew C.; Nakshabendi, Rahman; Kanar, Ozdemir; Hamer, Sean

    2017-01-01

    Background: Tumors within a Meckel diverticulum are a rare complication observed in only 0.5%-3.2% of symptomatic cases. The majority of tumors are benign, but some malignant tumors, such as gastrointestinal stromal tumors (GISTs) can occur. Case Report: We report the case of a 48-year-old female who presented with severe abdominal pain and nausea and was found to have a GIST arising from a Meckel diverticulum. Conclusion: The differential diagnosis of a pelvic mass in a middle-aged female presenting with gastrointestinal symptoms must remain broad. With an atypical presentation site, distinguishing benign tumors from malignant tumors such as GISTs is of paramount importance. PMID:28331460

  14. Molecular diagnostics in soft tissue sarcomas and gastrointestinal stromal tumors.

    PubMed

    Smith, Stephen M; Coleman, Joshua; Bridge, Julia A; Iwenofu, O Hans

    2015-04-01

    Soft tissue sarcomas are rare malignant heterogenous tumors of mesenchymal origin with over fifty subtypes. The use of hematoxylin and eosin stained sections (and immunohistochemistry) in the morphologic assessment of these tumors has been the bane of clinical diagnosis until recently. The last decade has witnessed considerable progress in the understanding and application of molecular techniques in refining the current understanding of soft tissue sarcomas and gastrointestinal stromal tumors beyond the limits of traditional approaches. Indeed, the identification of reciprocal chromosomal translocations and fusion genes in some subsets of sarcomas with potential implications in the pathogenesis, diagnosis and treatment has been revolutionary. The era of molecular targeted therapy presents a platform that continues to drive biomarker discovery and personalized medicine in soft tissue sarcomas and gastrointestinal stromal tumors. In this review, we highlight how the different molecular techniques have enhanced the diagnosis of these tumors with prognostic and therapeutic implications.

  15. Gastrointestinal pacemaker cell tumor (GIPACT): gastrointestinal stromal tumors show phenotypic characteristics of the interstitial cells of Cajal.

    PubMed Central

    Kindblom, L. G.; Remotti, H. E.; Aldenborg, F.; Meis-Kindblom, J. M.

    1998-01-01

    The interstitial cells of Cajal (ICC) form a complex cell network within the gastrointestinal tract wall where they function as a pacemaker system. Expression of the kit proto-oncogene is essential for the development of this system. The aim of our study was to examine the hypothesis that gastrointestinal stromal tumors differentiate toward cells with an ICC phenotype. Ultrastructurally, 58 stromal tumors were characterized and found to share many features with ICC. Seventy-eight stromal tumors were immunophenotyped, particularly with regard to the kit receptor. All 78 tumors revealed strong, homogeneous immunoreactivity for the kit receptor as did ICC of adjacent and control gastrointestinal walls. Focal hyperplasia and hypertrophy of kit receptor positive cells were also observed in the gastrointestinal wall adjacent to the tumors. CD34 immunoreactivity observed in interstitial cells surrounding Auerbach's ganglia suggests that a subpopulation of ICC is CD34 positive and may explain why 56 of 78 stromal tumors were CD34 positive. Thirty control tumors, including gastrointestinal leiomyomas and leiomyosarcomas, were all negative for the kit receptor. We conclude that gastrointestinal stromal tumors show striking morphological and immunophenotypic similarities with ICC and that they may originate from stem cells that differentiate toward a pacemaker cell phenotype. We propose that the noncommittal name "gastrointestinal stromal tumor" be replaced by gastrointestinal pacemaker cell tumor. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 PMID:9588894

  16. A gist of gastrointestinal stromal tumors: A review

    PubMed Central

    Rammohan, Ashwin; Sathyanesan, Jeswanth; Rajendran, Kamalakannan; Pitchaimuthu, Anbalagan; Perumal, Senthil-Kumar; Srinivasan, UP; Ramasamy, Ravi; Palaniappan, Ravichandran; Govindan, Manoharan

    2013-01-01

    Gastrointestinal stromal tumors (GISTs) have been recognized as a biologically distinctive tumor type, different from smooth muscle and neural tumors of the gastrointestinal tract (GIT). They constitute the majority of gastrointestinal mesenchymal tumors of the GIT and are known to be refractory to conventional chemotherapy or radiation. They are defined and diagnosed by the expression of a proto-oncogene protein detected by immunohistochemistry which serves as a crucial diagnostic and therapeutic target. The identification of these mutations has resulted in a better understanding of their oncogenic mechanisms. The remarkable antitumor effects of the molecular inhibitor imatinib have necessitated accurate diagnosis of GIST and their distinction from other gastrointestinal mesenchymal tumors. Both traditional and minimally invasive surgery are used to remove these tumors with minimal morbidity and excellent perioperative outcomes. The revolutionary use of specific, molecularly-targeted therapies, such as imatinib mesylate, reduces the frequency of disease recurrence when used as an adjuvant following complete resection. Neoadjuvant treatment with these agents appears to stabilize disease in the majority of patients and may reduce the extent of surgical resection required for subsequent complete tumor removal. The important interplay between the molecular genetics of GIST and responses to targeted therapeutics serves as a model for the study of targeted therapies in other solid tumors. This review summarizes our current knowledge and recent advances regarding the histogenesis, pathology, molecular biology, the basis for the novel targeted cancer therapy and current evidence based management of these unique tumors. PMID:23847717

  17. [Gastrointestinal stromal tumors: case reports and review of the literature].

    PubMed

    Bronzino, P; Colombini, M; Ferro, A; Gambetta, G; Gennaro, M; Ivaldi, L; Revetria, P

    2008-01-01

    The Authors describe four cases of gastrointestinal stromal tumours (GIST) two of them were localized in the stomach, the others in the ileum. GIST are neoplasms of mesenchymal origin which develop inside the wall of the digestive tract. The most frequent site is the stomach, followed by the small bowel; less commonly these tumors can affect the oesophagus, the colon and the rectum. GIST originate from precursors of the interstitial cells of Cajal, which are localized in the gastro-intestinal wall and are involved in the regulation of the peristalsis. The treatment is surgical resection. For advanced disease there is a new interesting treatment based on the imatinib, a tyrosine kinase inhibitor.

  18. Diagnosis and treatment of gastrointestinal stromal tumor extending to prostate

    PubMed Central

    Xu, Huan; Liu, Chong; Chen, Yanbo; Gu, Meng; Cai, Zhikang; Chen, Qi; Wang, Zhong

    2016-01-01

    Abstract Rationale: Gastrointestinal stromal tumor (GIST) is the neoplasm of gastrointestinal tract. Patient concerns: The patient complained about the retention of urinary. Diagnoses: GIST. Interventions: radical prostatectomy and the imatinib therapy. Outcomes: No recurrence and metastasis have been found during a 14-month follow-up. Lessons: comprehensive treatment is necessary for the GIST treatment. Furthermore, we summarize a review of the literature of GIST occurring in the prostate gland treated by different methods and 4 kinds of rare diseases in prostate. PMID:27861390

  19. Gastrointestinal Stromal Tumor Arising From a Gastric Duplication Cyst

    PubMed Central

    Machicado, Jorge; Davogustto, Giovanni

    2016-01-01

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

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

    PubMed Central

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

    2009-01-01

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

  1. Heterotopic Pancreatic Pseudocyst Radiologically Mimicking Gastrointestinal Stromal Tumor

    PubMed Central

    Sarsenov, Dauren; Tırnaksız, Mehmet Bülent; Doğrul, Ahmet Bülent; Tanas, Özlem; Gedikoglu, Gökhan; Abbasoğlu, Osman

    2015-01-01

    Heterotopic pancreas is a relatively common variant of foregut embryologic dystopia that can be described as pancreatic tissue found outside the normal anatomic location, being independent from vascular supply of normal pancreas. Having all features of pancreatic tissue except for the major duct structures, this ectopic tissue may be clinically recognized when pathologic changes take place. Inflammation, hemorrhagic or obstructive states, and eventually malignancy-related problems may become a diagnostic challenge for clinician and finally lead to consequences of misdiagnosis. In this article we will discuss a case of heterotopic pancreatic tissue located in gastric cardia, which was diagnosed preoperatively as gastrointestinal stromal tumor. PMID:25785332

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

    PubMed Central

    Yamamoto, Mami; Yamamoto, Kentaroh; Taketomi, Hirotaka; Yamamoto, Fumio; Yamamoto, Hiroshi

    2016-01-01

    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. PMID:27920659

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

    PubMed Central

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

    2014-01-01

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

  4. Gastrointestinal stromal tumor in an XYY/XY male.

    PubMed

    Limacher, Jean-Marc; Girard-Lemaire, Françoise; Jeandidier, Eric; Chenard-Neu, Marie-Pierre; Kassem, Maysoun; Flori, Elisabeth; Bergerat, Jean-Pierre

    2002-03-01

    A 32-year-old patient was diagnosed with a gastrointestinal stromal tumor of the small bowel. The pathologic diagnosis was confirmed by positive immunochemistry against CD34, and against CD117, the tyrosine-kinase c-kit. We performed a karyotypic analysis on the basis of the patient's tall stature and speech difficulties. One hundred thirty-two metaphases were obtained on PHA-stimulated peripheral blood; 123 of them presented an extra chromosome Y. Fluorescence in situ hybridization using a Y satellite III probe showed the presence of a sole copy of chromosome Y in the tumor cells precluding a direct relationship between the extra chromosome Y and the initiation of the tumor. This is, to our knowledge, the second occurrence of a nonhematologic malignancy reported in this genetic disorder. A review of the malignancies observed in men with the XYY constitution is presented.

  5. Liquid biopsy in gastrointestinal stromal tumors: a novel approach.

    PubMed

    Nannini, Margherita; Astolfi, Annalisa; Urbini, Milena; Biasco, Guido; Pantaleo, Maria A

    2014-08-14

    The role of molecular analysis in the management of gastrointestinal stromal tumors (GIST) remains indisputable. To date, tumor tissue extracted from specimens obtained by surgical or biopsy procedures has been the only source of the tumor DNA required for the molecular and genomic assessment of cancer. However, tumor tissue sampling has several clinical limitations: for example, the invasiveness of these procedures precludes repeated sampling. Thus, it is possible to obtain only a static molecular picture of the disease, a picture that lacks the inter- and intra-metastatic molecular heterogeneity that characterizes most GIST. In contrast, circulating tumor DNA obtained from a patient's bloodstream, known as liquid biopsy, can theoretically overcome the limitations of tissue biopsies and provide the same molecular and genomic information. GIST are recognized as a paradigm of molecular biology among solid tumors. Although few but promising data on liquid biopsy in GIST have been accumulated to date, these tumors may provide the optimal field for application of this challenging approach.

  6. Coexistence of gastrointestinal stromal tumor, esophageal and gastric cardia carcinomas.

    PubMed

    Zhou, Yong; Wu, Xu-Dong; Shi, Quan; Jia, Jing

    2013-03-28

    Gastric gastrointestinal stromal tumor (GIST), esophageal squamous cell carcinoma and gastric cardia adenocarcinoma are distinct neoplasms originating from different cell layers; therefore, simultaneous development of such carcinomas is relatively rare. Auxiliary examinations revealed coexistence of esophageal and gastric cardia carcinoma with lymph node metastasis in a 77-year-old man. Intraoperatively, an extraluminal tumor (about 6.0 cm × 5.0 cm × 6.0 cm) at the posterior wall of the gastric body, a tumor (about 2.5 cm × 2.0 cm) in the lower esophagus, and an infiltrative and stenosing tumor (about 1.0 cm × 2.0 cm) in the gastric cardia were detected. Wedge resection for extraluminal gastric tumor, radical esophagectomy for lower esophageal tumor, and cardiac resection with gastroesophageal (supra-aortic arch anastomoses) were performed. Postoperative histological examination showed synchronous occurrence of gastric GIST, esophageal squamous cell carcinoma, and gastric cardia adenocarcinoma. Furthermore, immunohistochemistry indicated strong staining for c-Kit/CD117, Dog-1, Ki-67 and smooth muscle, while expression of S-100 and CD34 was negative.

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

    PubMed

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

    2015-05-01

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

  8. CT Features of Colorectal Schwannomas: Differentiation from Gastrointestinal Stromal Tumors

    PubMed Central

    Kang, Ji Hee; Kim, Se Hyung; Kim, Young Hoon; Rha, Sung Eun; Hur, Bo Yun; Han, Joon Koo

    2016-01-01

    Purpose To find differential CT features of colorectal schwannomas from gastrointestinal stromal tumors (GISTs). Materials and Methods CT features of 13 pathologically proven colorectal schwannomas and 21 GISTs were retrospectively reviewed. The following CT items were analyzed: size, longitudinal and transverse location, shape, margin, homogeneity, necrosis, surface ulceration, calcification, degree of attenuation, the presence of enlarged lymph node (LN), and metastasis. Among the features, significant variables were evaluated using univariate statistical tests. The optimal cut-off point of tumor size was obtained by ROC analysis. Binary logistic regression analysis was used to find the most independent CT variables. Results Small size, non-rectum location, smooth margin, homogeneous high attenuation without necrosis, and the presence of enlarged LNs were found to be significant variables to differentiate schwannomas from GISTs (P<0.05). The optimized cut-off point for tumor size in distinguishing GISTs from schwannomas was 3.9 cm (AUC = 0.808, sensitivity = 66.7%, specificity = 92.3%, P<0.0001). Binary regression analysis revealed that only non-rectum location remained independent predictor for schwannomas differentiated from GISTs (odds ratio = 31.667, P = 0.001). Conclusion Colorectal schwannomas usually located in non-rectum and appear as small subepithelial nodules showing homogeneous high attenuation and smooth margin. Schwannomas exclusively accompany with enlarged LNs. PMID:28005903

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

    PubMed Central

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

    2016-01-01

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

  10. Proapoptotic activity of bortezomib in gastrointestinal stromal tumor cells.

    PubMed

    Bauer, Sebastian; Parry, Joshua A; Mühlenberg, Thomas; Brown, Matthew F; Seneviratne, Danushka; Chatterjee, Payel; Chin, Anna; Rubin, Brian P; Kuan, Shih-Fan; Fletcher, Jonathan A; Duensing, Stefan; Duensing, Anette

    2010-01-01

    Gastrointestinal stromal tumors (GIST) are caused by activating mutations in the KIT or PDGFRA receptor tyrosine kinase genes. Although >85% of GIST patients treated with the small-molecule inhibitor imatinib mesylate (Gleevec) achieve disease stabilization, complete remissions are rare and a substantial proportion of patients develop resistance to imatinib over time. Upregulation of soluble, non-chromatin-bound histone H2AX has an important role in imatinib-induced apoptosis of GIST cells. Additionally, H2AX levels in untreated GIST are maintained at low levels by a pathway that involves KIT, phosphoinositide 3-kinase, and the ubiquitin-proteasome system. In this study, we asked whether bortezomib-mediated inhibition of the ubiquitin-proteasome machinery could lead to upregulation of histone H2AX and GIST cell death. We show that bortezomib rapidly triggers apoptosis in GIST cells through a combination of mechanisms involving H2AX upregulation and loss of KIT protein expression. Downregulation of KIT transcription was an underlying mechanism for bortezomib-mediated inhibition of KIT expression. In contrast, the nuclear factor-kappaB signaling pathway did not seem to play a major role in bortezomib-induced GIST cell death. Significantly, we found that bortezomib would induce apoptosis in two imatinib-resistant GIST cell lines as well as a short-term culture established from a primary imatinib-resistant GIST. Collectively, our results provide a rationale to test the efficacy of bortezomib in GIST patients with imatinib-sensitive or -resistant tumors.

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

    ClinicalTrials.gov

    2013-06-03

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

  12. Diagnostic and treatment strategy for small gastrointestinal stromal tumors

    PubMed Central

    Goto, Osamu; Raut, Chandrajit Premanand; Yahagi, Naohisa

    2016-01-01

    Gastrointestinal stromal tumors (GISTs) are considered to be potentially malignant mesenchymal tumors of the gastrointestinal tract. Clinically relevant GISTs are rare; however, subclinical GISTs (mini‐GISTs) (1‐2 cm) and pathologic GISTs (micro‐GISTs) (<1 cm) are frequently reported. Most mini‐GISTs and almost all micro‐GISTs of the stomach may exhibit benign clinical behavior, and only mini‐GISTs with high‐risk features may progress. For this review, a provisional algorithm was used to propose diagnostic and treatment strategies for patients with small GISTs. Because surgery is the only potentially curative treatment, in its application for small GISTs, the principles of sarcoma surgery should be maintained, and cost effectiveness should be considered. Indications for surgery include GISTs measuring ≥2 cm, symptomatic GISTs, and mini‐GISTs with high‐risk features (irregular borders, cystic spaces, ulceration, echogenic foci, internal heterogeneity, and tumor progression during follow‐up); however, a preoperative pathologic diagnosis is infrequently obtained. For small intestinal and colorectal GISTs, surgery is indicated irrespective of size because of their greater malignant potential. Otherwise, mini‐GISTs without high‐risk features, micro‐GISTs, and small submucosal tumors measuring <5 cm without high‐risk features may be followed by periodical endoscopic ultrasonography. Although surgical approaches and operative methods are selected according to tumor size, location, growth pattern, and surgical teams, laparoscopic surgery has produced similar oncologic outcomes and is less invasiveness compared with open surgery. After resection, pathologic examination for diagnosis and risk assessment is mandatory, and genotyping is also recommended for high‐risk GISTs. Endoscopic resection techniques, although feasible, are not routinely indicated for most mini‐GISTs or micro‐GISTs. Cancer 2016;122:3110–8. © 2016 The Authors

  13. Recurrent epimutation of SDHC in gastrointestinal stromal tumors.

    PubMed

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

    2014-12-24

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

  14. [Gastrointestinal stromal tumors (GIST): at the forefront of targeted therapies].

    PubMed

    Emile, Jean-François

    2013-01-01

    Although gastrointestinal stromal tumors (GIST) are the most frequent sarcomas, they were usually not diagnosed before 1998. GIST derive from interstitial cells of Cajal, and may develop along the digestive tract, mainly from stomach and small intestine. GIST are characterized by the expression of KIT (CD117), and mutations KIT or PDGFRA are present in 85 % of cases. More than 150 different types of mutations have been reported. They are responsible for a constitutive activation of these tyrosine kinase receptors, in absence of their specific ligand. Detection of these mutations may help to confirm the diagnosis or to evaluate the prognosis. The mutations also have a predictive value. Indeed patients with metastatic GIST and duplication within exon 9 of KIT deserve to receive twice the dose of imatinib, while GIST with PDGFRA p.D842 V mutation are resistant to this drug. This review presents the main characteristics of GIST, and focus on the important insights of studies on GIST and their cell models in the field of oncology.

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

    PubMed

    O'Brien, Katie M; Orlow, Irene; Antonescu, Cristina R; Ballman, Karla; McCall, Linda; DeMatteo, Ronald; Engel, Lawrence S

    2013-01-01

    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 origins and

  16. Gastrointestinal Stromal Tumors, Somatic Mutations and Candidate Genetic Risk Variants

    PubMed Central

    O'Brien, Katie M.; Orlow, Irene; Antonescu, Cristina R.; Ballman, Karla; McCall, Linda; DeMatteo, Ronald; Engel, Lawrence S.

    2013-01-01

    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 origins

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

    MedlinePlus

    ... These treatments may include radiofrequency ablation (RFA; using electric currents to heat the tumor), or ethanol ablation ( ... Life Events College Relay For Life Donate a Car Ways to Give Memorial Giving Planned Giving Leadership ...

  18. Incidental detection of a bleeding gastrointestinal stromal tumor on Tc-99m red blood cell scintigraphy.

    PubMed

    Santhosh, Sampath; Bhattacharya, Anish; Gupta, Vikas; Singh, Rajinder; Radotra, Bishan Dass; Mittal, Bhagwant Rai

    2012-10-01

    The role of 99m-technetium labeled red blood cell (RBC) scintigraphy in acute gastro-intestinal bleed is well-established. The authors report a case of a bleeding gastrointestinal stromal tumor (GIST) incidentally discovered on Tc-99m RBC scintigraphy.

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

    PubMed

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

    2014-01-01

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

  20. Anti-tumor effects of the Notch pathway in gastrointestinal stromal tumors.

    PubMed

    Dumont, Amaury G; Yang, Yanwen; Reynoso, David; Katz, Daniela; Trent, Jonathan C; Hughes, Dennis P

    2012-09-01

    Gastrointestinal stromal tumors (GISTs) are driven by gain-of-function mutations of KIT or PDGFRa. The introduction of imatinib has significantly extended survival for patients. However, most patients develop resistances. Notch signaling is a conserved developmental pathway known to play a critical role in the development of several cancers, functioning as a tumor promoter or a tumor suppressor. Given that the normal progenitor cell for GIST, the interstitial cell of Cajal, has characteristics similar to those of cells of neuroendocrine origin, we hypothesized that Notch pathway impacts the biology of GIST cells. In this study, we retrovirally and pharmacologically manipulated the Notch pathway in human GIST cells. We also performed a retrospective analysis of a cohort on 15 primary tumors to determine the role of Hes1, a major target gene of Notch, as a prognostic marker for GIST. Constitutively, active intracellular domain of Notch1 (ICN1) expression potently induced growth arrest and downregulated KIT expression in vitro. Additionally, treatment with the histone deacetylase inhibitor suberoylanilide hydroxamic acid caused dose-dependent upregulation of Notch1 expression and a parallel decrease in viability in these cells. Retroviral silencing of downstream targets of Notch (dominant-negative Hes1) and pharmacological inhibition of Notch activation (γ-secretase inhibition) partially rescued GIST cells from suberoylanilide hydroxamic acid treatment. GIST patients with high Hes1 mRNA levels have a significantly longer relapse-free survival. These results identify a novel anti-tumor effect of Notch1 and cross talk between the Notch and KIT pathways. Thus, activation of this pathway by treatment with histone deacetylase inhibitors is an appealing potential therapeutic strategy for GISTs. Précis: This study is the first report of the tumor suppressor effects of Notch pathway in gastrointestinal stromal tumors via a negative feedback with the oncogene KIT and may

  1. Small gastrointestinal stromal tumor in the stomach: identification of precursor for clinical gastrointestinal stromal tumor using c-kit and α-smooth muscle actin expression.

    PubMed

    Mikami, Tetuo; Nemoto, Yuta; Numata, Yoshiko; Hana, Kiyomi; Nakada, Norihiro; Ichinoe, Masaaki; Murakumo, Yoshiki; Okayasu, Isao

    2013-12-01

    Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the digestive tract. To find precursors for clinical GISTs of the stomach, small gastric stromal tumors of less than 3 cm were collected and examined immunohistochemically with analysis of the KIT mutation. Sixty-eight of 74 lesions were classified into 4 representative groups according to the expression of c-kit and α-smooth muscle actin (αSMA): group A, c-kit diffusely positive and αSMA negative (18 cases); group B, c-kit diffusely positive and αSMA focally positive (13); group C, c-kit focally positive and αSMA diffusely positive (27); and group D, c-kit negative and αSMA diffusely positive (10). Of the 4 groups, groups A and B of c-kit diffuse expression showed higher cellularity and labeling indices of p27(Kip1) and Ki-67 than did groups C and D of diffuse αSMA expression. Incidence of KIT exon 11 mutation in groups A and B was 86% (25/29), whereas that in groups C and D was 0% (0/20). Small gastric stromal tumors with c-kit diffuse expression were considered precursors for clinical GIST because they were significantly different from c-kit focally positive or negative tumors. The mutation of KIT is considered as an early event in tumorigenesis of GIST.

  2. Gastrointestinal Stromal Tumor Showing Intense Tracer Uptake on PSMA PET/CT.

    PubMed

    Noto, Benjamin; Weckesser, Matthias; Buerke, Boris; Pixberg, Michaela; Avramovic, Nemanja

    2017-03-01

    A 70-year-old man with suspected prostate cancer was referred for Ga-PSMA-HBED-CC PET/CT (short PSMA PET/CT) for staging of tumor extent. Apart from vivid tracer uptake in the prostate gland and osseous metastasis, PSMA PET/CT revealed a large soft tissue mass with calcifications in the left upper abdomen showing intense tracer uptake. Histologic examination revealed the mass to be a gastrointestinal stromal tumor.

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

    PubMed

    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.

  4. Clinical activity of regorafenib in PDGFRA-mutated gastrointestinal stromal tumor.

    PubMed

    Grellety, Thomas; Kind, Michèle; Coindre, Jean-Michel; Italiano, Antoine

    2015-11-01

    Gastrointestinal stromal tumor (GIST) is the most frequent mesenchymal tumor of the gastrointestinal tract and one of the most frequent sarcoma. Mutually exclusive KIT and PDGFRA mutations are central events in GIST pathogenesis, and their understanding is crucial because specific treatment targeting oncogenic KIT and PDGFRA activation (especially imatinib) has become available. The most frequent PDGFRA mutation (D842V) is associated with primary resistance to imatinib. Data related to regorafenib efficacy in PDGFRA-mutated GIST are lacking. We report here a case report of a prolonged response with regorafenib in a patient with a PDGFRA-mutated GIST.

  5. Lichenoid drug eruption caused by imatinib mesylate in a Chinese patient with gastrointestinal stromal tumor.

    PubMed

    Luo, Jing-Ru; Xiang, Xiao-Jun; Xiong, Jian-Ping

    2016-09-01

    Imatinib mesylate, the first agent approved for the treatment of unresectable or metastatic gastrointestinal stromal tumor, is a tyrosine kinase inhibitor targeting (KIT) and the platelet-derived growth factor receptor-α and -β. However, imatinib administration can be accompanied by various adverse events. Here we report a case of Lichenoid drug eruption (LDE) that appeared 24 weeks after commencement of imatinib in a 73-year-old man with gastrointestinal stromal tumor (GIST). The skin lesions were distributed over his face, trunk and limbs, which improved only after discontinuation of imatinib therapy. To the best of our knowledge, this is the first report of imatinib-induced LDE in the Chinese population.

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

    PubMed Central

    DeCaprio, James A.; Duensing, Anette

    2014-01-01

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

  7. Skull Metastasis of Gastric Gastrointestinal Stromal Tumor Successfully Managed by Surgery

    PubMed Central

    Park, Inkeun; Chung, Dong Hae; Yoo, Chan Jong; Shin, Dong Bok

    2017-01-01

    Gastrointestinal stromal tumors (GISTs) are rare, but are the most common mesenchymal neoplasm of the gastrointestinal tract. The most common sites of metastasis are liver and peritoneum, while bone metastasis is rare. We report on a patient with skull metastasis after seven years of treatment with imatinib for metastatic GIST. She underwent metastasectomy consisting of craniectomy with excision of the mass, and cranioplasty and continued treatment with imatinib and sunitinib, without evidence of cranial recurrence. She died of pneumonia sepsis one year after metastasectomy. Skull metastasis of GIST is a very rare presentation, and an aggressive multidisciplinary approach should be considered whenever possible. PMID:28061498

  8. [Gastrointestinal stromal tumors: report of a clinical case and review of the literature].

    PubMed

    Bronzino, P; Cassinelli, G; Arena, E; Rassu, P C; Partipilo, F; Rusca, I; Cuneo, A E; Casaccia, M

    2002-01-01

    In this case report, the Authors describe a case of stromal gastric tumour, in a male 65 years old, who presented gastrointestinal bleeding. Gastro-Intestinal Stromal Tumors (GISTs) are neoplasm with an incidence of 1-3 per cent of the digestive tract malignant neoplasms. The rarity of this disease, its visceral wall localization, the histopathological characteristics make the diagnosis difficult. Moreover there is no correlation between the behaviour of these neoplasms and the histologic features. Surgery represents the main treatment for GISTs based on complete resection, followed by a long-term follow-up. Chemotherapy and radiotherapy don't seem to play a crucial role in the treatment of these neoplasms. A new treatment with inhibitors of the tyrosinekinase is under discussion. Follow-up represents the only way to evaluate the effective behaviour of the disease, due to the lack of classic prognostic factors impact.

  9. Primary gastrointestinal stromal tumor of the liver: A case report and review of the literature

    PubMed Central

    Cheng, Xiaobin; Chen, Dong; Chen, Wenbin; Sheng, Qinsong

    2016-01-01

    Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors located in the alimentary tract. A small portion of GISTs are observed in extra-gastrointestinal regions, primarily in the omentum, mesentery and retroperioneum, and these types of GISTs are referred to as extra-gastrointestinal stromal tumors. The present study reports of a patient with unique primary liver GIST. The patient underwent en bloc resection and post-operative administration of imatinib, and subsequently experienced a good prognosis. The present case is followed by a brief review of reported cases of liver GISTs identified in the literature. The literature revealed that primary liver GISTs are usually large in size and possess a high mitotic index, which contributes to malignant characterization, thus classifying these tumors as high-risk. En bloc resection remains the mainstay of treatment for resectable primary liver GISTs. However, the prognosis of these patients is not favorable. Perioperative administration of imatinib may be useful to a certain extent, and interventional therapy, including radiofrequency ablation, should be considered. PMID:27698856

  10. Current Concepts in Non-Gastrointestinal Stromal Tumor Soft Tissue Sarcomas: A Primer for Radiologists

    PubMed Central

    Jagannathan, Jyothi P.; O'Neill, Ailbhe; Tirumani, Harika; Tirumani, Sree Harsha

    2017-01-01

    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. PMID:28096721

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed Central

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

    2014-01-01

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

  13. Epigenetics in gastrointestinal stromal tumors: clinical implications and potential therapeutic perspectives.

    PubMed

    Sioulas, Athanasios D; Vasilatou, Diamantina; Pappa, Vasiliki; Dimitriadis, George; Triantafyllou, Konstantinos

    2013-11-01

    Gastrointestinal stromal tumors (GIST) represent the most common mesenchymal neoplasms affecting the gastrointestinal tract. Activating mutations in either the KIT or PDGFRa gene are the principal oncogenic triggers with the former accounting for more than 80 % of cases. In the small subset of GIST that are wild type for both the aforementioned changes, other germline or somatic mutations have been identified. GIST exhibit a highly variable clinical behavior and the main prognostic determinants are tumor size, mitotic rate, and location. It is, however, strongly believed that, beyond classic genetics, additional epigenetic phenomena such as DNA hypomethylation and hypermethylation, microRNA alterations, and chromatin modifications underlie GIST tumorigenesis and influence the clinical course and response to standard treatment. This review aims to illuminate current advances in terms of epigenetics in GIST, as well as possible implications in prognosis and therapeutics.

  14. Familial and multiple gastrointestinal stromal tumors with fair response to a half-dose of imatinib.

    PubMed

    Bamba, Shigeki; Hirota, Seiichi; Inatomi, Osamu; Ban, Hiromitsu; Nishimura, Takashi; Shioya, Makoto; Imaeda, Hirotsugu; Nishida, Atsushi; Sasaki, Masaya; Murata, Satoshi; Andoh, Akira

    2015-01-01

    Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. Since our first report in 1998, approximately 30 families with multiple GISTs due to a germline gain-of-function mutation of c-kit have been reported. We herein present a case of a family with multiple GISTs that have a germline c-kit mutation in exon 11 (Del-Val560) in two siblings. One of the patients showed a fair response to treatment with a half-dose of imatinib (200 mg/day). There are few reports describing the response to imatinib in familial GISTs and this drug appears to be a promising therapeutic option.

  15. Gastric gastrointestinal stromal tumor (GIST) incidentally found and resected during laparoscopic sleeve gastrectomy.

    PubMed

    Beltran, Marcelo A; Pujado, Blazenko; Méndez, Pedro E; Gonzáles, Francisco J; Margulis, David I; Contreras, Mario A; Cruces, Karina S

    2010-03-01

    The incidence of incidental pathology found during laparoscopic bariatric surgery has been estimated to be around 2%, and gastric gastrointestinal stromal tumors (GISTs) have been found in 0.8% of patients, constituting a rather uncommon finding. Safe laparoscopic resection of gastric GISTs is an established procedure and has been described associated to gastric Roux-en-Y bypass for morbid obesity. We discuss one case of a gastric GIST incidentally discovered during laparoscopic sleeve gastrectomy for morbid obesity. The procedure was performed via laparoscopy, and the patient recovered without any complication. Currently, the patient has lost weight according to what was expected, is asymptomatic, and free of disease.

  16. Gastrointestinal stromal tumors of the stomach with extensive calcification: report of two cases.

    PubMed

    Kim, Hyun-Soo; Sung, Ji-Youn; Park, Won Seo; Kim, Youn Wha

    2012-01-01

    Gastrointestinal stromal tumors (GISTs) can present with focal calcification. However, the presence of extensive calcification that constitutes the major portion of a GIST is extremely rare and can be associated with diagnostic pitfalls. We herein present the first two cases of rare gastric GIST with predominantly calcified components that mimicked pancreatic solid and pseudopapillary neoplasms with extensive calcification. In patients presenting with hyper-dense, heavily calcified masses in the abdominal cavity, the possibility of GIST should be considered in the differential diagnosis. A careful search for cellular areas and the judicious application of immunostaining will thus make it possible to make a correct diagnosis.

  17. Imatinib-induced Ototoxicity in a Patient with Gastrointestinal Stromal Tumor (GIST)

    PubMed Central

    Wasif, Komal; Wasif, Nawal

    2016-01-01

    Imatinib (Gleevec) is a biological agent that is approved for the treatment of chronic myeloid leukemia (CML) as well as gastrointestinal stromal tumor (GIST). The most frequently seen adverse effects in patients treated with imatinib include superficial edema, muscle cramps, musculoskeletal pain, rash, fatigue, headache, abdominal pain, and joint pain. Ototoxicity has rarely been reported except in two cases. We report a case of bilateral irreversible sensorineural hearing loss (SNHL) caused by imatinib in a patient receiving this agent in the adjuvant setting. This case underlines the importance of early recognition of this potential toxicity that can impact the quality of life. PMID:27909636

  18. Gastrointestinal stromal tumors and KIT-positive mesenchymal cells in the omentum.

    PubMed

    Sakurai, S; Hishima, T; Takazawa, Y; Sano, T; Nakajima, T; Saito, K; Morinaga, S; Fukayama, M

    2001-07-01

    Gastrointestinal stromal tumor (GIST) is currently considered to be derived from the interstitial cells of Cajal (ICC). To test the hypothesis that omental mesenchymal tumor is also a type of GIST, we evaluated the expression of specific molecules in GIST, and c-kit gene mutation in omental mesenchymal tumors, and we identified a possible counterpart of ICC in the omentum. Immunohistochemically, all of the omental mesenchymal tumors (n = 5) were positive for both KIT and CD34, and three of the five tumors were also positive for an embryonic form of smooth-muscle myosin heavy chain (SMemb). Polymerase chain reaction-single-strand conformational polymorphism analysis (PCR-SSCP) and direct sequencing revealed mutations in c-kit gene exon 11 in all five tumors. As for the ICC counterparts in the omentum, there were some KIT-positive mesenchymal cells resembling ICC at the surface of the omentum. Double fluorescence immunostaining, using anti-KIT polyclonal antibodies and monoclonal antibodies against other molecules, demonstrated that KIT-, CD34- and SMemb-positive cells were present just beneath the mesothelial cells of the omentum. These results show that omental mesenchymal tumor corresponds to GIST of the omentum, and that KIT-positive bipolar mesenchymal cells may be a counterpart of ICC in the gastrointestinal tract. Identification of a new type of KIT-positive mesenchymal cell in the omentum may lead to the discovery of a new physiological role for this organ.

  19. Synchronous gastric gastrointestinal stromal tumor (GIST) and other primary neoplasms of gastrointestinal tract: report of two cases.

    PubMed

    Kaur, Ramneet; Bhalla, Sunita; Nundy, Samiran; Jain, Sunila

    2013-01-01

    Gastrointestinal stromal tumors (GIST) are the most common mesenchymal neoplasms of the gastrointestinal tract with a malignant potential. However, uncommonly they can be associated with synchronous tumors of different histogenesis. We herein report two cases of gastric GIST with synchronous tumors. The first case is of a 50-year-old male patient who was suspected with GIST of stomach and was incidentally found to have an associated duodenal neuroendo-crine neoplasm. The second case is of a 62-year-old male who, while undergoing surgery for a primary colon adenocarcinoma, was incidentally detected to have a coexistent gastric GIST initially suspected to be a metastatic nodule. Coexistence of gastric GIST with neuroendocrine tumor is extremely rare. To the best of our knowledge this is the second case of gastric GIST coexisting with duodenal neuroendocrine tumor to be reported in the literature. Similarly, association of GIST with adenocarcinoma is uncommon. We herein analyze the pathological findings of two such cases, and we review the malignant potential of these synchronous tumors.

  20. Antitumor effects in gastrointestinal stromal tumors using photodynamic therapy with a novel glucose-conjugated chlorin.

    PubMed

    Tanaka, Mamoru; Kataoka, Hiromi; Yano, Shigenobu; Ohi, Hiromi; Moriwaki, Kazuhiro; Akashi, Haruo; Taguchi, Takahiro; Hayashi, Noriyuki; Hamano, Shingo; Mori, Yoshinori; Kubota, Eiji; Tanida, Satoshi; Joh, Takashi

    2014-04-01

    Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the gastrointestinal tract. Except for surgical resection, no effective treatment strategies have been established. Photodynamic therapy (PDT) consists of intravenous administration of a photosensitizer, activated by a specific wavelength of light, which produces reactive oxygen species that directly kill tumor cells. We analyzed the efficacy of PDT using a newly developed photosensitizer, 5,10,15,20-tetrakis [4-[β-d-glucopyranosylthio-2,3,5,6-tetrafluorophenyl]-2,3,[methano[N-methyl] iminomethano] chlorin (H(2)TFPC-SGlc), for the GIST treatment. Various photosensitizers were administered in vitro to GIST (GIST-T1) and fibroblast (WI-38) cells, followed by irradiation, after which cell death was compared. We additionally established xenograft mouse models with GIST-T1 tumors and examined the accumulation and antitumor effects of these photosensitizers in vivo. In vitro, the expression of the glucose transporters GLUT1, GLUT3, and GLUT4, the cellular uptake of H(2)TFPC-SGlc, and apoptosis mediated by PDT with H(2)TFPC-SGlc were significantly higher in GIST-T1 than in WI-38 cells. In vivo, H(2)TFPC-SGlc accumulation was higher in xenograft tumors of GIST-T1 cells than in the adjacent normal tissue, and tumor growth was significantly suppressed following PDT. PDT with novel H(2)TFPC-SGlc is potentially useful for clinical applications about the treatment of GIST.

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

    PubMed

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

    2016-06-21

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

  2. Case report of pneumatosis intestinalis secondary to sunitinib treatment for refractory gastrointestinal stromal tumor.

    PubMed

    Jarkowski, Anthony; Hare, Ryan; Francescutti, Valerie; Wilkinson, Neal; Khushalani, Nikhil

    2011-10-01

    Pneumatosis intestinalis (PI) occurs when inter-luminal air enters the bowel wall of the gastrointestinal tract via a mucosal defect. The condition is caused by numerous disease states, direct trauma, and various drugs. When PI is secondary to drug therapy, discontinuation of the offending agent results in the resolution of PI. We report on the case of a 73-year-old male with a history of refractory gastrointestinal stromal tumor experiencing PI while on sunitinib treatment. PI was noted via computed tomography (CT) scans 68 days after starting sunitinib therapy and showed near complete resolution on a follow up CT performed one month after discontinuing sunitinib. Given that a CT scan performed five months prior to the initiation of sunitinib did not show PI, lack of abdominal symptoms in our patient, and resolution of PI after discontinuing sunitinib, the cause of PI in our patient was likely due to sunitinib treatment.

  3. Gastrointestinal stromal tumors: evolving role of the multidisciplinary team approach in management.

    PubMed

    Reichardt, Peter; Morosi, Carlo; Wardelmann, Eva; Gronchi, Alessandro

    2012-08-01

    Gastrointestinal stromal tumors (GISTs) are rare tumors of the GI tract arising from mesenchymal cells. Treatment options include surgical resection and medical therapy with imatinib. A summary of National Comprehensive Cancer Network and European Society of Medical Oncology clinical practice guidelines relating to GIST management are presented here. A multidisciplinary team of physicians is essential to the successful treatment of GIST. Evidence supports multidisciplinary team management with a gastroenterologist, surgeon, medical oncologist, pathologist and radiologist. Consultations between them are recommended to ensure optimal care of patients with GIST. The role for individual core team workers is highlighted. The benefits of multidisciplinary disease management of patients include reducing recurrent disease, optimizing timing of surgery and organ preservation, prolonging survival for the patient and enhancing response to targeted therapies.

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

    PubMed Central

    Ravegnini, Gloria; Nannini, Margherita; Sammarini, Giulia; Astolfi, Annalisa; Biasco, Guido; Pantaleo, Maria A.; Hrelia, Patrizia; Angelini, Sabrina

    2015-01-01

    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). PMID:26184165

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

    PubMed

    Ravegnini, Gloria; Nannini, Margherita; Sammarini, Giulia; Astolfi, Annalisa; Biasco, Guido; Pantaleo, Maria A; Hrelia, Patrizia; Angelini, Sabrina

    2015-07-09

    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).

  6. Development of enterohepatic fistula after embolization in ileal gastrointestinal stromal tumor: a case report.

    PubMed

    Lee, Yun Ho; Koo, Ja Seol; Jung, Chang Ho; Chung, Sang Yoon; Lee, Jae Joong; Kim, Seung Young; Hyun, Jong Jin; Jung, Sung Woo; Choung, Rok Seon; Lee, Sang Woo; Choi, Jai Hyun

    2013-11-21

    Gastrointestinal stromal tumor (GIST) is a rare mesenchymal tumor of the gastrointestinal tract that has been associated with the formation of fistulas to adjacent organs in few case reports. However, GIST with enterohepatic fistula has not been reported. Here we report the case of an enterohepatic fistula that occurred after embolization of a liver mass originating in the distal ileum. An 87-year-old woman was hospitalized for melena. On initial conventional endoscopy, a bleeding focus in the gastrointestinal tract was not found. Because of massive hematochezia, enteroscopy was performed through the anus. A protruding, ulcerative mass was found in the distal ileum that was suspected to be the source of the bleeding; a biopsy sample was taken. Electrocoagulation was not successful in controlling the bleeding; therefore, embolization was performed. After embolization, the patient developed a high fever and severe abdominal tenderness with rebound tenderness. Follow-up abdominopelvic computed tomography revealed an enterohepatic fistula between the liver and distal ileum. The fistula was treated surgically by segmental resection of the distal ileum and unlooping of the liver mass.

  7. Supraclavicular lymph node metastases from malignant gastrointestinal stromal tumor of the jejunum: A case report with review of the literature

    PubMed Central

    Ma, Chi; Hao, Shao-Long; Liu, Xin-Cheng; Nin, Jin-Yao; Wu, Guo-Chang; Jiang, Li-Xin; Fancellu, Alessandro; Porcu, Alberto; Zheng, Hai-Tao

    2017-01-01

    Gastrointestinal stromal tumors (GISTs) represent the most common mesenchymal tumors of the alimentary tract. These tumors may have different clinical and biological behaviors. Malignant forms usually spread via a hematogenous route, and lymph node metastases rarely occur. Herein, we report a patient with a jejunal GIST who developed supraclavicular lymph node metastasis. We conclude that lymphatic diffusion via the mediastinal lymphatic station to the supraclavicular lymph nodes can be a potential metastatic route for GISTs. PMID:28348499

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

    NASA Astrophysics Data System (ADS)

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

    2016-07-01

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

  9. Asian Consensus Guidelines for the Diagnosis and Management of Gastrointestinal Stromal Tumor

    PubMed Central

    Koo, Dong-Hoe; Ryu, Min-Hee; Kim, Kyoung-Mee; Yang, Han-Kwang; Sawaki, Akira; Hirota, Seiichi; Zheng, Jie; Zhang, Bo; Tzen, Chin-Yuan; Yeh, Chun-Nan; Nishida, Toshirou; Shen, Lin; Chen, Li-Tzong; Kang, Yoon-Koo

    2016-01-01

    Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors originating in the gastrointestinal tract. With the introduction of molecular-targeted therapy for GISTs which has yielded remarkable outcomes, these tumors have become a model of multidisciplinary oncological treatment. Although Western clinical guidelines are available for GISTs, such as those published by the National Comprehensive Cancer Network (NCCN) and the European Society of Medical Oncology (ESMO), the clinical situations in Asian countries are different from those in Western countries in terms of diagnostic methods, surgical approach, and availability of new targeted agents. Accordingly, we have reviewed current versions of several GIST guidelines published by Asian countries (Japan, Korea, China, and Taiwan) and the NCCN and ESMO and discussed the areas of dissensus. We here present the first version of the Asian GIST consensus guidelines that were prepared through a series of meetings involving multidisciplinary experts in the four countries. These guidelines provide an optimal approach to the diagnosis and management of GIST patients in Asian countries. PMID:27384163

  10. Heavily calcified gastrointestinal stromal tumors: Pathophysiology and implications of a rare clinicopathologic entity

    PubMed Central

    Salati, Massimiliano; Orsi, Giulia; Reggiani Bonetti, Luca; Di Benedetto, Fabrizio; Longo, Giuseppe; Cascinu, Stefano

    2017-01-01

    Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract, and are characterized by a broad spectrum of clinical, histological and molecular features at presentation. Although focal and scattered calcifications are not uncommon within the primary tumor mass, heavy calcification within a GIST is rarely described in the literature and the clinical-biological meaning of this feature remains unclear. Cases with such an atypical presentation are challenging and may be associated with diagnostic pitfalls. Herein, we report a gastric GIST with the unusual presentation of prominent calcifications that was identified incidentally on imaging during a post-trauma diagnostic work-up. The patient underwent laparoscopic surgery with a radical resection of the mass, which was subsequently characterized by histological analysis as spindle-shaped tumor cells, positive for CD117/c-KIT, CD34 and DOG1, and with calcified areas. Given the intermediate risk of recurrence, no adjuvant therapy was recommended and the patient underwent regular follow-up for 22 mo, with no evidence of relapse. Our case can be considered of interest because of the rarity of clinical presentation and the uniquely large size of the GIST at diagnosis (longest diameter exceeding 9 cm). In closing, we discuss the pathophysiology and clinical implications of calcifications in GISTs by reviewing the most up-to-date relevant literature. PMID:28344749

  11. Evidence for Ca2+-Regulated ATP Release in Gastrointestinal Stromal Tumors

    PubMed Central

    Berglund, Erik; Berglund, David; Akcakaya, Pinar; Ghaderi, Mehran; Daré, Elisabetta; Berggren, Per-Olof; Köhler, Martin; Aspinwall, Craig A.; Lui, Weng-Onn; Zedenius, Jan; Larsson, Catharina; Bränström, Robert

    2013-01-01

    Gastrointestinal stromal tumors (GISTs) are thought to originate from the electrically active pacemaker cells of the gastrointestinal tract. Despite the presence of synaptic-like vesicles and proteins involved in cell secretion it remains unclear whether GIST cells possess regulated release mechanisms. The GIST tumor cell line GIST882 was used as a model cell system, and stimulus-release coupling was investigated by confocal microscopy of cytoplasmic free Ca2+ concentration ([Ca2+]i), flow cytometry, and luminometric measurements of extracellular ATP. We demonstrate that GIST cells have an intact intracellular Ca2+-signaling pathway that regulates ATP release. Cell viability and cell membrane integrity was preserved, excluding ATP leakage due to cell death and suggesting active ATP release. The stimulus-secretion signal transduction is at least partly dependent on Ca2+ influx since exclusion of extracellular Ca2+ diminishes the ATP release. We conclude that measurements of ATP release in GISTs may be a useful tool for dissecting the signal transduction pathway, mapping exocytotic components, and possibly for the development and evaluation of drugs. Additionally, release of ATP from GISTs may have importance for tumor tissue homeostasis and immune surveillance escape. PMID:23499741

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

    PubMed Central

    Garlipp, Benjamin; Bruns, Christiane J.

    2014-01-01

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

  13. Ménétrier disease and gastrointestinal stromal tumors: hyperproliferative disorders of the stomach

    PubMed Central

    Coffey, Robert J.; Washington, Mary Kay; Corless, Christopher L.; Heinrich, Michael C.

    2007-01-01

    Ménétrier disease and gastrointestinal stromal tumors (GISTs) are hyperproliferative disorders of the stomach caused by dysregulated receptor tyrosine kinases (RTKs). In Ménétrier disease, overexpression of TGF-α, a ligand for the RTK EGFR, results in selective expansion of surface mucous cells in the body and fundus of the stomach. In GISTs, somatic mutations of the genes encoding the RTK KIT (or PDGFRA in a minority of cases) result in constitutive kinase activity and neoplastic transformation of gut pacemaker cells (interstitial cells of Cajal). On the basis of the involvement of these RTKs in the pathogenesis of these disorders, Ménétrier disease patients have been effectively treated with a blocking monoclonal antibody specific for EGFR and GIST patients with KIT and PDGFRA tyrosine kinase inhibitors. PMID:17200708

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

    PubMed

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

    2011-01-01

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

  15. Gastrointestinal stromal tumor of the stomach with axillary lymph node metastasis: A case report

    PubMed Central

    Kubo, Naoki; Takeuchi, Nobumichi

    2017-01-01

    Gastrointestinal stromal tumors (GISTs) are the most common type of gastrointestinal mesenchymal tumors, although metastasis to the perigastric lymph nodes is relatively rare, compared with liver or peritoneal metastasis. In this report, we describe a case of stomach GIST with a solitary simultaneous metastasis in the left axillary lymph node. A 68-year-old man was diagnosed with a large upper-stomach GIST, and computed tomography and positron emission tomography revealed masses in the left axilla and right mediastinum. We did not detect evidence of metastases to the liver, or other sites including the perigastric lymph nodes, although findings from the surgically resected axillary lymph nodes were compatible with GIST metastasis. Treatment using imatinib markedly reduced the gastric and mediastinal lesions, and this response persisted for 3 years. The patient subsequently experienced rapid growth of the gastric lesion without mediastinal or axilla recurrence, which required palliative surgery. Despite continuing medical treatment (sunitinib and regorafenib), the patient died of liver metastases 23 mo after the surgery. Based on our findings, it appears that the axillary lymph nodes can be a potential metastatic site for GIST metastasis. PMID:28321172

  16. Gastrointestinal stromal tumors in kidney transplant recipients: Report of two cases and literature review.

    PubMed

    Cheung, Chi Yuen; Lo, Stanley Hok King; Chan, Ching Kit; Li, Fu Keung; Cheng, Ignatius Kum Po; Chau, Ka Foon

    2017-02-01

    Gastrointestinal stromal tumors (GISTs) are the most common primary mesenchymal gastrointestinal neoplasms. However, GISTs occurring in kidney transplant recipients, including their treatment and outcome, are rarely described in literature. We hereby report two kidney transplant recipients with GISTs. Our first patient was diagnosed with high-risk epithelioid gastric GIST 2 years after kidney transplant. He received everolimus after resection and remained disease-free for 2 years before liver metastasis was confirmed. Imatinib therapy was planned but he died of fulminant pneumonia shortly. Our second patient was diagnosed with spindle cell GISTs in the mesentery 1 year after kidney transplant. Only partial response was obtained with imatinib as new lesions continued to develop. Withdrawal of cyclosporine and introduction of sirolimus resulted in complete shrinkage of existing tumors and no new lesions. He remained disease-free for more than 10 years. Combination therapy consisting of imatinib and inhibitors of mammalian target of rapamycin (mTORi) seems to be safe and effective in kidney transplant recipients. However, therapeutic drug monitoring of mTORi is essential to avoid nephrotoxicity. Further trials addressing the optimal dosage of imatinib and mTORi in kidney transplant recipients are recommended.

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed

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

    2016-02-09

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

  19. Sunitinib in the treatment of gastrointestinal stromal tumor: patient selection and perspectives

    PubMed Central

    Mulet-Margalef, Nuria; Garcia-del-Muro, Xavier

    2016-01-01

    Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract. In advanced setting and after progression to imatinib, the multi-targeted receptor tyrosine kinase inhibitor sunitinib has clearly demonstrated a clinical benefit in terms of response rate and progression-free survival with an acceptable toxicity profile. The recommended schedule for sunitinib administration is 50 mg per day 4 weeks ON and 2 weeks OFF; however, potential alternative schedules are also reviewed in the present article. Several biomarkers have been explored to better select candidates for sunitinib therapy, such as the value of early changes in standardized uptake value assessed by positron emission tomography with 18F-fluorodeoxyglucose, circulating biomarkers, clinical biomarkers such as the appearance of arterial hypertension during treatment that correlates with better outcomes, and the GIST genotype. GISTs with KIT mutations at exon 9 and the so-called wild-type GISTs seem to better respond to sunitinib. Nonetheless, further investigation is required to confirm these findings as well as to understand the mechanisms of sunitinib resistance such as the development of new KIT mutations or conformational changes in KIT receptor. PMID:28008275

  20. KIT exon 11 deletion-inversions represent complex mutations in gastrointestinal stromal tumors.

    PubMed

    Lasota, Jerzy; Miettinen, Markku

    2007-05-01

    Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. KIT expression and mutational KIT activation have been documented in a majority of GISTs. Most mutations have been found in KIT juxtamembrane domain encoded by exon 11. Recently, we have identified three, complex KIT exon 11 mutations previously unreported in GISTs. These mutations consisted of several nucleotide deletions accompanied by insertions of inverted complementary DNA strand sequences. All three mutations were found in the 5' part of KIT exon 11. At the protein level, these mutations lead to the same end result: in-frame loss and insertion of a number of amino acids and could be considered examples of deletion-insertion. Although proper description of these mutations at the genomic level is a complex task and requires an individual approach, the uniform name deletion-inversion is suggested for this type of mutation, based on the present study. The frequency of deletion-inversions among KIT exon 11 mutant GISTs was estimated to be <0.5%, based on evaluation of 700 KIT exon 11 mutants. Molecular events leading to formation of deletion-inversions remain elusive and should be studied further.

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

    PubMed Central

    2014-01-01

    Background Gastrointestinal stromal tumor (GIST) is the most common sarcoma and its treatment with imatinib has served as the paradigm for developing targeted anti-cancer therapies. Despite this success, imatinib-resistance has emerged as a major problem and therefore, the clinical efficacy of other drugs has been investigated. Unfortunately, most clinical trials have failed to identify efficacious drugs despite promising in vitro data and pathological responses in subcutaneous xenografts. We hypothesized that it was feasible to develop orthotopic patient-derived xenografts (PDXs) from resected GIST that could recapitulate the genetic heterogeneity and biology of the human disease. Methods Fresh tumor tissue from three patients with pathologically confirmed GISTs was obtained immediately following tumor resection. Tumor fragments (4.2-mm3) were surgically xenografted into the liver, gastric wall, renal capsule, and pancreas of immunodeficient mice. Tumor growth was serially assessed with ultrasonography (US) every 3-4 weeks. Tumors were also evaluated with positron emission tomography (PET). Animals were sacrificed when they became moribund or their tumors reached a threshold size of 2500-mm3. Tumors were subsequently passaged, as well as immunohistochemically and histologically analyzed. Results Herein, we describe the first model for generating orthotopic GIST PDXs. We have successfully xenografted three unique KIT-mutated tumors into a total of 25 mice with an overall success rate of 84% (21/25). We serially followed tumor growth with US to describe the natural history of PDX growth. Successful PDXs resulted in 12 primary xenografts in NOD-scid gamma or NOD-scid mice while subsequent successful passages resulted in 9 tumors. At a median of 7.9 weeks (range 2.9-33.1 weeks), tumor size averaged 473±695-mm3 (median 199-mm3, range 12.6-2682.5-mm3) by US. Furthermore, tumor size on US within 14 days of death correlated with gross tumor size on necropsy. We also

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

    PubMed Central

    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

    Background 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. Case presentation 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. Conclusion 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. PMID:17229322

  3. Oncogenic Kit signaling and therapeutic intervention in a mouse model of gastrointestinal stromal tumor

    PubMed Central

    Rossi, Ferdinand; Ehlers, Imke; Agosti, Valter; Socci, Nicholas D.; Viale, Agnes; Sommer, Gunhild; Yozgat, Yasemin; Manova, Katia; Antonescu, Cristina R.; Besmer, Peter

    2006-01-01

    Kit receptor-activating mutations are critical in the pathogenesis of gastrointestinal stromal tumors (GIST). We investigated mechanisms of oncogenic Kit signaling and the consequences of therapeutic intervention in a mouse model of human GIST. Treatment of GIST mice with imatinib decreased cell proliferation and increased apoptosis in the tumor. Analysis of tumor tissue from imatinib-treated mice showed diminished phosphatidylinositol 3-kinase (PI3-kinase) and mammalian target of rapamycin (mTOR) signaling suggesting that oncogenic Kit signaling critically contributes to the translational response in GIST. Treatment with RAD001 (everolimus), an mTOR inhibitor, diminished the translational response and cell proliferation in tumor lesions, pointing to mTOR inhibition as a therapeutic approach for imatinib-resistant GIST. Analysis of RNA expression profiles in GIST lesions with and without imatinib treatment showed changes in expression of IFN-inducible genes and cell cycle regulators. These results convincingly show that KitV558Δ/+ mice represent a unique faithful mouse model of human familial GIST, and they demonstrate the utility of these mice for preclinical investigations and to elucidate oncogenic signaling mechanisms by using genetic approaches and targeted pharmacological intervention. PMID:16908864

  4. A Case of a Gastrointestinal Stromal Tumor Diagnosed at the Postpartum Period

    PubMed Central

    Canda, Aras Emre; Karadeniz, Emre; Yavuzsen, Tugba; Sagol, Ozgul; Obuz, Funda; Canda, Mehmet Serefettin

    2016-01-01

    Introduction. We discuss a rare gastrointestinal stromal tumor (GIST) case detected at the 10th postpartum week and we want to pay attention to the challenges and improvements in the diagnosis, surgery, chemotherapy, and follow-up of this rare tumor accompanied with the review of the current literature. Case Presentation. A 32-year-old multiparous woman presented with abdominal swelling 10 weeks after her second vaginal birth. Abdominal examination revealed a mass starting from the pelvic level and extending to the right upper quadrant. Radiological examinations showed a solid, multiloculated, and hypervascular mass starting from the pelvis and extending to the transverse colon. En bloc mass with a 20 cm jejunal segment resection and a left pelvic side wall peritonectomy with omentectomy was performed. The pathologic examination revealed a high-risk GIST which originated from the jejunum and disseminated to the peritoneum. The patient has been given imatinib 400 mg/day since then. She did not reveal any progression during the 15-month follow-up postoperatively. Conclusion. GIST tumors are rare and there is not sufficient information in the literature regarding its management. In this patient having high risk GIST and GIST sarcomatosis we successfully treated the patient by surgery and adjuvant imatinib chemotherapy. PMID:27957364

  5. Integrative Genomic Characterization and a Genomic Staging System for Gastrointestinal Stromal Tumors

    PubMed Central

    Ylipää, Antti; Hunt, Kelly K.; Yang, Jilong; Lazar, Alexander J. F.; Torres, Keila E.; Lev, Dina Chelouche; Nykter, Matti; Pollock, Raphael E.; Trent, Jonathan; Zhang, Wei

    2010-01-01

    Gastrointestinal stromal tumors (GISTs) were historically grouped with leiomyosarcomas (LMSs) based on their morphological similarities, but recently they have been unequivocally established as a distinct type of sarcoma based on the molecular features and response to imatinib treatment. To gain further insight into the genomic differences between GISTs and LMSs, we mapped gene copy number aberrations (CNAs) in 42 GISTs and 30 LMSs and integrated them with gene expression profiles. Our studies revealed distinct patterns of CNAs between GISTs and LMSs. Losses in chromosomes 1p, 14q, 15q, and 22q were significantly more frequent in GISTs than in LMSs (P < 0.001), whereas losses in chromosomes 10 and 16 as well as gains in 1q, 14q, and 15q (P < 0.001) were more common in LMSs. By integrating CNAs with gene expression data and clinical information, we found several clinically relevant CNAs that were prognostic of survival in patients with GIST. Furthermore, GISTs were categorized into four groups according to an accumulating pattern of genetic alterations. Many key cellular pathways were differently expressed in the four groups and the patients had increasingly worse prognosis as the extent of genomic alterations increased. These findings lead us to propose a new tumor-progression genetic staging system termed Genomic Instability Stage (GIS) to complement the current prognostic predictive system based on tumor size, mitotic index (MI), and KIT mutation. PMID:20818650

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed

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

    2013-06-01

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

  8. Neoadjuvant imatinib in locally advanced gastrointestinal stromal tumors of the stomach: report of three cases.

    PubMed

    Oh, Ji Seon; Lee, Jae-Lyun; Kim, Mi-Jung; Ryu, Min-Hee; Chang, Heung Moon; Kim, Tae Won; Jang, Se Jin; Yook, Jeong Hwan; Oh, Sung Tae; Kim, Byung Sik; Kang, Yoon-Koo

    2006-01-01

    Neoadjuvant imatinib therapy used to treat locally advanced or metastatic gastrointestinal stromal tumors (GI ST) remains under active investigation. We studied three cases of locally advanced gastric GISTs treated with imatinib on a neoadjuvant basis, followed by a complete surgical resection. Three patients were diagnosed with locally advanced unresectable GIST of the stomach and were started on imatinib 400 mg/day. After the imatinib treatment, partial responses were achieved in all patients and the tumors were considered resectable. Surgical resection was done after 7, 11, and 8 months of imatinib therapy, respectively. In one case, a metastatic liver lesion was detected during the imatinib treatment using computed tomography scans, so the imatinib therapy was maintained for 11 months postoperatively. In the other two patients without distant metastasis, imatinib treatment was not restarted after surgery. Mutational analysis revealed a mutation in exon 11 of the c-kit gene in two patients, and wild-type c-kit and PDGFRA in one patient. During pathology review of all three cases, we noted several features common to imatinib treatment. There was no evidence of tumor recurrence in all three patients at respective follow-up visits of 22, 15, and 7 months. These results suggest that the neoadjuvant imatinib therapy is a potentially curative approach for selected patients with locally advanced GIST.

  9. Genomic and transcriptomic analysis of imatinib resistance in gastrointestinal stromal tumors

    PubMed Central

    Takahashi, Tsuyoshi; Elzawahry, Asmaa; Mimaki, Sachiyo; Furukawa, Eisaku; Nakatsuka, Rie; Nakamura, Hiromi; Nishigaki, Takahiko; Serada, Satoshi; Naka, Tetsuji; Hirota, Seiichi; Shibata, Tatsuhiro; Tsuchihara, Katsuya

    2017-01-01

    Gastrointestinal stromal tumors represent the most common mesenchymal tumor of the digestive tract, driven by gain‐of‐function mutations in KIT. Despite its proven benefits, half of the patients treated with imatinib show disease progression within 2 years due to secondary resistance mutations in KIT. It remains unclear how the genomic and transcriptomic features change during the acquisition of imatinib resistance. Here, we performed exome sequencing and microarray transcription analysis for four imatinib‐resistant cell lines and one cell line briefly exposed to imatinib. We also performed exome sequencing of clinical tumor samples. The cell line briefly exposed to imatinib exhibited few single‐nucleotide variants and copy‐number alterations, but showed marked upregulation of genes related to detoxification and downregulation of genes involved in cell cycle progression. Meanwhile, resistant cell lines harbored numerous genomic changes: amplified genes related to detoxification and deleted genes with cyclin‐dependent kinase activity. Some variants in the resistant samples were traced back to the drug‐sensitive samples, indicating the presence of ancestral subpopulations. The subpopulations carried variants associated with cell death. Pre‐existing cancer cells with genetic alterations promoting apoptosis resistance may serve as a basis whereby cancer cells with critical mutations, such as secondary KIT mutations, can establish full imatinib resistance. © 2017 The Authors Genes, Chromosomes and Cancer Published by Wiley Periodicals, Inc. PMID:27997714

  10. Fine needle aspiration biopsy of gastrointestinal stromal tumor presenting as an umbilical mass (Sister Mary Joseph's Nodule).

    PubMed

    Scudeler, Donizete; Wakely, Paul E

    2006-04-01

    The Sister Mary Joseph (SMJ) nodule is a clinical sign of metastatic cancer involving the umbilicus. The vast majority of these instances represent adenocarcinomas arising from ovarian or colorectal primaries. We present a patient who presented with ascites and the SMJ lesion that turned out to be a metastatic gastrointestinal stromal tumor after fine needle aspiration biopsy was performed. The lesion was subsequently histologically confirmed. Gastrointestinal stroma tumor involving the umbilicus is exceedingly uncommon and only rarely presents in this fashion. The cytomorphological features, differential diagnosis, and comparison with the tissue specimen are made.

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

    PubMed Central

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

    2012-01-01

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

  12. GLP-2 receptors in human disease: high expression in gastrointestinal stromal tumors and Crohn's disease.

    PubMed

    Körner, Meike; Rehmann, Ruth; Reubi, Jean Claude

    2012-11-25

    Peptide hormones of the glucagon-like peptide (GLP) family play an increasing clinical role, as reported for GLP-1 in diabetes therapy and insulinoma diagnostics. GLP-2, despite its known trophic and anti-inflammatory intestinal actions translated into preliminary clinical studies using the GLP-2 analogue teduglutide for treatment of short bowel syndrome and Crohn's disease, remains poorly characterized in terms of expression of its receptor in tissues of interest. Therefore, the GLP-2 receptor expression was assessed in 237 tumor and 148 non-neoplastic tissue samples with in vitro receptor autoradiography. A GLP-2 receptor expression was present in 68% of gastrointestinal stromal tumors (GIST). Furthermore, GLP-2 receptors were identified in the intestinal myenteric plexus, with significant up-regulation in active Crohn's disease. The GLP-2 receptors in GIST may be used for clinical applications like in vivo targeting with radiolabelled GLP-2 analogues for imaging and therapy. Moreover, the over-expressed GLP-2 receptor in the myenteric plexus may represent the morphological correlate of the clinical target of teduglutide in Crohn's disease.

  13. Drug Repurposing Identifies a Synergistic Combination Therapy with Imatinib Mesylate for Gastrointestinal Stromal Tumor

    PubMed Central

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

    2014-01-01

    Gastrointestinal Stromal Tumor (GIST) is a rare and therefore often neglected disease. Introduction of the kinase inhibitor, imatinib mesylate (IM) 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 impacted the overall survival of patients with advanced disease. We employed a novel, focused, drug repurposing effort for GIST including IM-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 IM. F-AMP induces DNA damage, annexin V and caspase 3/7 activities as the cytotoxic effects on GIST cells, including IM-resistant GIST cells. F-AMP and IM combination treatment showed greater inhibition of GIST cell proliferation when compared to IM alone and F-AMP alone. Successful in vivo experiments confirmed the combination of IM with F-AMP enhanced the antitumor effects compared to IM 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 IM or for treatment of IM-refractory tumors. PMID:25122069

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

    PubMed Central

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

    2015-01-01

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

  15. Gastrointestinal stromal tumors (GISTs): SEAP-SEOM consensus on pathologic and molecular diagnosis.

    PubMed

    Martin-Broto, J; Martinez-Marín, V; Serrano, C; Hindi, N; López-Guerrero, J A; Ramos-Asensio, R; Vallejo-Benítez, A; Marcilla-Plaza, D; González-Cámpora, R

    2016-12-09

    Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the digestive tract, with an incidence of 1.1 cases/100,000 inhabitants/year. A group of experts from the Spanish Society of Pathology and the Spanish Society of Oncology met to discuss a brief update on GISTs and agree on aspects relating to the pathological and molecular diagnosis of these tumors. GISTs are generally solitary, well-circumscribed lesions of variable size (<10 mm-35 cm) that may present with intra- or extra-luminal parietal growth or a mixed-type (hourglass) growth pattern. Histologically, they are unencapsulated neoplasms displaying expansive growth and spindle-shaped (70%), epithelioid (20%), or mixed cellularity (10%). Mitotic activity is generally moderate or low and should be evaluated only in areas with high cellularity or higher mitotic frequency. The great majority of GISTs harbour mutually exclusive activating mutations in genes coding for the type III receptor tyrosine kinases KIT and PDGFRA; less commonly, GISTs have also been reported to display mutations elsewhere, including BRAF and NF1 and SDH-complex genes. The method most widely used to detect KIT and PDGFRA mutations is amplification of the exons involved by polymerase chain reaction followed by direct sequencing (Sanger method) of these amplification products. Molecular analyses should always specify the type of analysis performed, the region or mutations evaluated, and the sensitivity of the detection method employed.

  16. Promoter methylation of PCDH10 by HOTAIR regulates the progression of gastrointestinal stromal tumors

    PubMed Central

    Lee, Na Keum; Lee, Jung Hwa; Kim, Won Kyu; Yun, Seongju; Youn, Young Hoon; Park, Chan Hyuk; Choi, Yun Young; Kim, Hogeun; Lee, Sang Kil

    2016-01-01

    HOTAIR, a long non-coding RNA (lncRNA), plays a crucial role in tumor initiation and metastasis by interacting with the PRC2 complex and the modulation of its target genes. The role of HOTAIR in gastrointestinal stromal tumors (GISTs) is remains unclear. Herein we investigate the mechanism of HOTAIR in the genesis and promotion of GISTs. The expression of HOTAIR was found to be higher in surgically resected high-risk GISTs than that in low- and intermediate-risk GISTs. Using GIST-T1 and GIST882 cells, we demonstrated that HOTAIR repressed apoptosis, was associated with cell cycle progression, and controlled the invasion and migration of GIST cells. Using a gene expression microarray and lists of HOTAIR-associated candidate genes, we suggested that protocadherin 10 (PCDH10) is a key molecule. PCDH10 expression was significantly decreased in GIST-T1 and GIST882 cells, possibly as a consequence of hypermethylation. We observed that HOTAIR induced PCDH10 methylation in a SUZ12-dependent manner. In this study, we found that the malignant character of GISTs was initiated and amplified by PCDH10 in a process regulated by HOTAIR. In summary, our findings imply that PCDH10 and HOTAIR may be useful markers of disease progression and therapeutic targets. PMID:27659532

  17. Contrast-enhanced (endoscopic) ultrasound and endoscopic ultrasound elastography in gastrointestinal stromal tumors

    PubMed Central

    Ignee, Andre; Jenssen, Christian; Hocke, Michael; Dong, Yi; Wang, Wen-Ping; Cui, Xin-Wu; Woenckhaus, Matthias; Iordache, Sevastita; Saftoiu, Adrian; Schuessler, Gudrun; Dietrich, Christoph F.

    2017-01-01

    Background and Objectives: Gastrointestinal stromal tumors (GISTs) represent the largest group of subepithelial tumors (SET) of the upper gastrointestinal (GI) tract. They may show malignant behavior, in contrast to other SET. Endoscopic ultrasound (EUS) is frequently used to characterize SET. With the introduction of contrast-enhanced ultrasound (CEUS) into EUS (CE-EUS), distinct enhancement patterns can be detected. In the presented study, the characteristic features of CE-EUS in GIST are analyzed and compared with those of other SET. Materials and Methods: Consecutive patients from four centers with SET of the upper and middle GI tract were included and received endoscopic or transcutaneous CEUS. The results were compared with EUS-guided tissue acquisition, forceps biopsy, or surgical resection. Results: Forty-two out of 62 (68%) patients had SET of the stomach, 17/62 (27%) of the small intestine, 2/62 (3%) of the esophagus, and 1/62 (2%) extraintestinal. Eighty-one percent underwent surgery. Leiomyoma was found in 5/62 (8%) and GIST in 57/62 patients (92%). Thirty-nine out of 57 (68%) patients had GIST lesions in the stomach, 17/57 (30%) had GIST of the small intestine, and 1/57 (2%) patients had extraintestinal GISTs. GIST size was 62.6 ± 42.1 (16–200) mm. Hyperenhancement had a sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of 98%, 100%, 100%, 93%, and 98% for the diagnosis of GIST. Fifty out of 57 patients with GIST (88%) showed avascular areas in the center of the lesions. Conclusion: CE-EUS and CEUS show hyperenhancement and avascular areas in a high percentage of GIST but not in leiomyoma. Thus, GIST and leiomyoma can be discriminated accurately. PMID:28218202

  18. DOG1 for the diagnosis of gastrointestinal stromal tumor (GIST): Comparison between 2 different antibodies.

    PubMed

    Lopes, Lisandro F; West, Robert B; Bacchi, Livia M; van de Rijn, Matt; Bacchi, Carlos E

    2010-07-01

    Gastrointestinal stromal tumor (GIST) is the most common mesenchymal neoplasm of the gastrointestinal tract. Discovered on GIST-1 (DOG1) is a recently described protein expressed in GISTs irrespective of mutation status. The aim of this study was to investigate the immunohistochemical expression of DOG1 using 2 different monoclonal antibodies (DOG1.1 and the commercially available K9 antibody) in 668 GIST cases and to compare the results with the expression of KIT. DOG1 and KIT expression also were studied in most human normal tissues and several nonmesenchymal and mesenchymal tumors other than GIST. KIT was expressed in 643 (96.3%) GISTs. DOG1.1 and K9 were positive in 538 (80.5%) and 642 (96.1%) GIST cases, respectively. In 25 (3.7%) KIT-negative GIST cases, DOG1 was expressed in 5 (20.0%) and 19 (76.0%) using DOG1.1 and K9 antibodies, respectively. Only 0.9% of GISTs were negative for KIT, DOG1.1, and K9. Most normal human tissues did not reveal KIT and DOG1 expression. DOG1.1 was positive in only 2 of 57 synovial sarcomas and 1 of 61 soft tissue leiomyosarcomas. K9 was positive in 5 of 57 synovial sarcomas, 1 of 14 angiosarcomas, 1 of 61 soft tissue leiomyosarcomas, 3 of 4 adenoid cystic carcinomas of the head and neck, and in myoepithelial cells of 9 of 11 fibroadenomas of the breast. In conclusion, the commercially available K9 is of great utility for the diagnosis of most KIT-negative GISTs, and the combination of both KIT and K9 antibody in a panel of immunohistochemistry can define the diagnosis of GIST in more than 99% of cases.

  19. Is laparoscopic resection the appropriate management of a jejunal gastrointestinal stromal tumor (GIST)? Report of a case.

    PubMed

    Pitiakoudis, Michail; Zezos, Petros; Courcoutsakis, Nikos; Papanas, Nikolaos; Giatromanolaki, Alexandra; Sivridis, Efthimios; Kouklakis, Georgios; Simopoulos, Constantinos

    2010-10-01

    A 51-year-old female patient presented with iron deficiency anemia. Upper and lower gastrointestinal endoscopy were unremarkable. Computed tomography enteroclysis showed an ovoid 3×4-cm jejunal tumor with intraluminal protrusion and exophytic growth pattern, without lymphadenopathy or metastatic disease. Laparoscopic resection of the tumor was successfully carried out. Histologically, a mesenchymal tumor composed of spindle cells with an interlacing bundle pattern and high-mitotic activity greater than 10 mitoses/50 high-power fields were observed. The immunohistochemistry showed that the tumor was KIT (CD117)-, vimentin-, smooth muscle actin-, and S-100-positive, whereas it was CD34-negative. These findings were consistent with the features of a gastrointestinal stromal tumor. The patient had an uneventful postoperative course, and after 10 months of follow-up, she is well without any evidence of tumor recurrence.

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

    PubMed Central

    2010-01-01

    Background 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. Methods 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. Results 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. Conclusions 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

  1. Gastric gastrointestinal stromal tumor with incomplete duplication cyst - a case with possibility of neoplasia in fetal-period malformed tissues.

    PubMed

    Lewitowicz, Piotr; Matykiewicz, Jaroslaw; Koziel, Dorota; Gluszek, Stanislaw Z; Sosnowski, Zbigniew; Horecka-Lewitowicz, Agata; Nasierowska-Guttmejer, Anna

    2015-03-01

    The coincidence of GIST and other gastric malignancies are documented well but arising GIST from congenital anomalies is still rarity in literature. To date, only a few papers have been concerned on the possibility of arising neoplasms from duplication cyst of gastrointestinal tract. There, are dominating usual cancers, neuroendocrine cancers or lymphomas but GIST has been noted only once. Here, we report a case of 73 years old female-patient with typical gastric stromal tumor comprised centrally locked an incomplete duplication cyst.

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

    PubMed

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

    2014-06-01

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

  3. A Screen for Epigenetically Silenced microRNA Genes in Gastrointestinal Stromal Tumors

    PubMed Central

    Nojima, Masanori; Kai, Masahiro; Yamamoto, Eiichiro; Maruyama, Reo; Nobuoka, Takayuki; Nishida, Toshirou; Kanda, Tatsuo; Taguchi, Takahiro; Hasegawa, Tadashi; Tokino, Takashi; Hirata, Koichi; Suzuki, Hiromu; Shinomura, Yasuhisa

    2015-01-01

    Background Dysregulation of microRNA (miRNA) has been implicated in gastrointestinal stromal tumors (GISTs) but the mechanism is not fully understood. In this study, we aimed to explore the involvement of epigenetic alteration of miRNA genes in GISTs. Methods GIST-T1 cells were treated with 5-aza-2’-deoxycytidine (5-aza-dC) and 4-phenylbutyric acid (PBA), after which miRNA expression profiles were analyzed using TaqMan miRNA arrays. DNA methylation was then analyzed using bisulfite pyrosequencing. The functions of miRNAs were examined using MTT assays, wound-healing assays, Boyden chamber assays and Matrigel invasion assays. Gene expression microarrays were analyzed to assess effect of ectopic miRNA expression in GIST-T1 cells. Results Of the 754 miRNAs analyzed, 61 were significantly upregulated in GIST-T1 cells treated with 5-aza-dC plus PBA. Among those, 21 miRNA genes were associated with an upstream CpG island (CGI), and the CGIs of miR-34a and miR-335 were frequently methylated in GIST-T1 cells and primary GIST specimens. Transfection of miR-34a or miR-335 mimic molecules into GIST-T1 cells suppressed cell proliferation, and miR-34a also inhibited migration and invasion by GIST-T1 cells. Moreover, miR-34a downregulated a number of predicted target genes, including PDGFRA. RNA interference-mediated knockdown of PDGFRA in GIST-T1 cells suppressed cell proliferation, suggesting the tumor suppressive effect of miR-34a is mediated, at least in part, through targeting PDGFRA. Conclusions Our results suggest that miR-34a and miR-335 are candidate tumor suppressive miRNAs in GISTs, and that they are frequent targets of epigenetic silencing in GISTs. PMID:26214687

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

    PubMed Central

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

    2009-01-01

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

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed Central

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

    2016-01-01

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

  8. ZNF-Mediated Resistance to Imatinib Mesylate in Gastrointestinal Stromal Tumor

    PubMed Central

    Zhou, Yan; von Mehren, Margaret; Godwin, Andrew K.

    2013-01-01

    Although imatinib mesylate (IM) has transformed the treatment of gastrointestinal stromal tumors (GIST), many patients experience primary/secondary drug resistance. In a previous study, we identified a gene signature, consisting mainly of Kruppel-associated box (KRAB) domain containing zinc finger (ZNF) transcriptional repressors that predict short-term response to IM. To determine if these genes have functional significance, a siRNA library targeting these genes was constructed and applied to GIST cells in vitro. These screens identified seventeen “IM sensitizing genes” in GIST cells (sensitization index (SI) <0.85 ratio of drug/vehicle) with a false discovery rate (FDR) <15%, including twelve ZNF genes, the majority of which are located within the HSA19p12–13.1 locus. These genes were shown to be highly specific to IM and another tyrosine kinase inhibitor (TKI), sunitinib, in GIST cells. In order to determine mechanistically how these ZNFs might be modulating response to IM, RNAi approaches were used to individually silence genes within the predictive signature in GIST cells and expression profiling was performed. Knockdown of the 14 IM-sensitizing genes (10 ZNFs) universally led to downregulation of six genes, including TGFb3, periostin, and NEDD9. These studies implicate a role of KRAB-ZNFs in modulating response to TKIs in GIST. PMID:23372733

  9. Kinase genotype analysis of gastric gastrointestinal stromal tumor cytology samples using targeted next-generation sequencing.

    PubMed

    Gleeson, Ferga C; Kipp, Benjamin R; Kerr, Sarah E; Voss, Jesse S; Graham, Rondell P; Campion, Michael B; Minot, Douglas M; Tu, Zheng J; Klee, Eric W; Lazaridis, Konstantinos N; Henry, Michael R; Levy, Michael J

    2015-01-01

    Gastric gastrointestinal stromal tumors (GISTs) usually contain the mast/stem cell growth factor receptor Kit gene (KIT) or platelet-derived growth factor receptor A (PDGFRA) mutations that can be targeted by, or mediate resistance to, imatinib. Diagnostic material often is obtained by endoscopic ultrasound-guided fine-needle aspiration, which often is unsuitable for molecular analysis. We investigated whether targeted next-generation sequencing (NGS) can be used in multiplex genotype analysis of cytology samples collected by endoscopic ultrasound-guided fine-needle aspiration. We used the Ion AmpliSeq V2 Cancer Hotspot NGS Panel (Life Technologies, Carlsbad, CA) to identify mutations in more than 2800 exons from 50 cancer-associated genes in GIST samples from 20 patients. We identified KIT mutations in 58% of samples (91% in exon 11 and 9% in exon 17) and PDGFRA mutations in 26% (60% in exon 18 and 40% in exon 12); 16% of samples had no mutations in KIT or PDGFRA. No pathogenic alterations were found in PIK3CA, BRAF, KRAS, NRAS, or FGFR3. We predicted that 32% of patients would have primary resistance to imatinib, based on mutations in exon 17 of KIT, exon 18 of PDGFRA (D842V), or no mutation in either gene. Targeted NGS of cytology samples from GISTs is feasible and provides clinically relevant data about kinase genotypes that can help guide individualized therapy.

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

    PubMed

    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.

  11. NCCN Task Force Report: Update on the Management of Patients with Gastrointestinal Stromal Tumors

    PubMed Central

    Demetri, George D.; von Mehren, Margaret; Antonescu, Cristina R.; DeMatteo, Ronald P.; Ganjoo, Kristen N.; Maki, Robert G.; Pisters, Peter W.T.; Raut, Chandrajit P.; Riedel, Richard F.; Schuetze, Scott; Sundar, Hema M.; Trent, Jonathan C.; Wayne, Jeffrey D.

    2014-01-01

    The standard of care for managing patients with gastrointestinal stromal tumors (GISTs) rapidly changed after the introduction of effective molecularly targeted therapies involving tyrosine kinase inhibitors (TKIs), such as imatinib mesylate and sunitinib malate. A better understanding of the molecular characteristics of GISTs have improved the diagnostic accuracy and led to the discovery of novel immunomarkers and new mechanisms of resistance to TKI therapy, which in turn have resulted in the development of novel treatment strategies. To address these issues, the NCCN organized a task force consisting of a multidisciplinary panel of experts in the fields of medical oncology, surgical oncology, molecular diagnostics, and pathology to discuss the recent advances, identify areas of future research, and recommend an optimal approach to care for patients with GIST at all stages of disease. The task force met for the first time in October 2003 and again in December 2006 and October 2009. This supplement describes the recent developments in the field of GIST as discussed at the October 2009 meeting. PMID:20457867

  12. Endoscopic submucosal dissection for silent gastric Dieulafoy lesions mimicking gastrointestinal stromal tumors

    PubMed Central

    Chen, Xue; Cao, Hailong; Wang, Sinan; Wang, Dan; Xu, Mengque; Piao, Meiyu; Wang, Bangmao

    2016-01-01

    Abstract Background: Dieulafoy lesion is a rare but serious cause of gastrointestinal hemorrhage. However, some cases can be occasionally found without bleeding during the endoscopic screening, and the management remains unclear. The aim of this article was to report the efficacy and safety of endoscopic submucosal dissection (ESD) for silent gastric Dieulafoy lesions, which presented as protrusion lesions mimicking gastrointestinal stromal tumors (GISTs). Methods: Data from the patients with gastric protrusion lesions who underwent ESD from September 2008 to April 2016 in General Hospital, Tianjin Medical University, China were recorded. Seven cases with pathological diagnosis of Dieulafoy lesion without bleeding were enrolled for further analysis. Results: A total of 7 patients (2 males and 5 females) with mean age of 57.7 ± 4.15 years were pathologically diagnosed as Dieulafoy lesion. Four of the lesions were located in gastric antrum, 2 in the fundus, and 1 in the body of stomach, respectively. The mean sizes of the Dieulafoy lesions under white light endoscopy and endoscopic ultrasonography (EUS) were 1.06 ± 0.28 and 0.84 ± 0.29 cm. The origins of these lesions were submucosa (6/7, 85.7%) and muscularis propria (1/7, 14.3%). Three of them appeared with mixed echo under EUS, 3 with hypoechogenicity, and 1 with hyperechogenicity. En bloc complete resection was achieved in all the lesions by ESD with average time of 76.00 ± 16.86 minutes, and no intraoperative bleeding happened. In addition, all patients were followed up for 1 to 53 months, and no recurrence or long-term complications was observed. Conclusion: Therefore, ESD can be an effective and safe treatment for silent gastric Dieulafoy lesions with clinical presentations of submucosal protrusion lesions mimicking GISTs. PMID:27603399

  13. Clinicopathological features and prognosis of coexistence of gastric gastrointestinal stromal tumor and gastric cancer

    PubMed Central

    Liu, Zhen; Liu, Shushang; Zheng, Gaozan; Yang, Jianjun; Hong, Liu; Sun, Li; Fan, Daiming; Zhang, Hongwei; Feng, Fan

    2016-01-01

    Abstract The coexistence of gastric gastrointestinal stromal tumor (GIST) and gastric cancer is relatively high, and its prognosis is controversial due to the complex and variant kinds of presentation. Thus, the present study aimed to explore the clinicopathological features and prognostic factors of gastric GIST with synchronous gastric cancer. From May 2010 to November 2015, a total of 241 gastric GIST patients were retrospectively enrolled in the present study. The patients with coexistence of gastric GIST and gastric cancer were recorded. The clinicopathological features and prognoses of patients were analyzed. Among 241 patients, 24 patients had synchronous gastric cancer (synchronous group) and 217 patients did not (no-synchronous group). The synchronous group presented a higher percentage of elders (66.7% vs 39.6%, P = 0.001) and males (87.5% vs 48.4%, P < 0.001) than the no-synchronous group. The tumor diameter, mitotic index, and National Institutes of Health degree were also significantly different between the 2 groups (all P < 0.05). The 5-year disease-free survival and disease-specific survival rates of synchronous group were significantly lower than those of no-synchronous group (54.9% vs 93.5%, P < 0.001; 37.9% vs 89.9%, P < 0.001, respectively). However, the 5-year overall survival rates between synchronous and gastric cancer groups were comparable (37.9% vs 57.6%, P = 0.474). The coexistence of gastric GIST and gastric cancer was common in elder male patients. The synchronous GIST was common in low-risk category. The prognosis of gastric GIST with synchronous gastric cancer was worse than that of primary-single gastric GIST, but was comparable with primary-single gastric cancer. PMID:27828865

  14. Insulin-like growth factor 1 receptor is a potential therapeutic target for gastrointestinal stromal tumors

    PubMed Central

    Tarn, Chi; Rink, Lori; Merkel, Erin; Flieder, Douglas; Pathak, Harsh; Koumbi, Daphne; Testa, Joseph R.; Eisenberg, Burton; von Mehren, Margaret; Godwin, Andrew K.

    2008-01-01

    A subset of gastrointestinal stromal tumors (GISTs) lack gain-of-function mutations in c-KIT and PDGFRα. These so-called wild-type (WT) GISTs tend to be less responsive to imatinib-based therapies and have a poor prognosis. We identified amplification of IGF1R in a SNP analysis of GIST and thus studied its potential as a therapeutic target in WT and mutant GIST. Expression of IGF1R and downstream effectors in clinical GIST samples was examined by using immunoblots and immunohistochemistry. The roles of IGF1R signaling in GIST and viability were analyzed by using NVP-AEW541, an inhibitor of IGF1R, alone and in combination with imatinib, or via siRNA silencing of IGF1R. IGF1R was strongly overexpressed, and IGF1R amplification was detected at a significantly higher frequency in WT GISTs, including a pediatric WT GIST, compared with mutant GISTs (P = 0.0173 and P = 0.0163, respectively). Inhibition of IGF1R activity in vitro with NVP-AEW541 or down-regulation of expression with siIGF1R led to cytotoxicity and induced apoptosis in GIST cell lines via AKT and MAPK signaling. Combination of NVP-AEW541 and imatinib in GIST cell lines induced a strong cytotoxicity response. Our results reveal that IGF1R is amplified and the protein is overexpressed in WT and pediatric GISTs. We also demonstrate that the aberrant expression of IGF1R may be associated with oncogenesis in WT GISTs and suggest an alternative and/or complementary therapeutic regimen in the clinical management of all GISTs, especially in a subset of tumors that respond less favorably to imatinib-based therapy. PMID:18550829

  15. Clinicopathological features and prognosis of coexistence of gastric gastrointestinal stromal tumor and gastric cancer.

    PubMed

    Liu, Zhen; Liu, Shushang; Zheng, Gaozan; Yang, Jianjun; Hong, Liu; Sun, Li; Fan, Daiming; Zhang, Hongwei; Feng, Fan

    2016-11-01

    The coexistence of gastric gastrointestinal stromal tumor (GIST) and gastric cancer is relatively high, and its prognosis is controversial due to the complex and variant kinds of presentation. Thus, the present study aimed to explore the clinicopathological features and prognostic factors of gastric GIST with synchronous gastric cancer.From May 2010 to November 2015, a total of 241 gastric GIST patients were retrospectively enrolled in the present study. The patients with coexistence of gastric GIST and gastric cancer were recorded. The clinicopathological features and prognoses of patients were analyzed.Among 241 patients, 24 patients had synchronous gastric cancer (synchronous group) and 217 patients did not (no-synchronous group). The synchronous group presented a higher percentage of elders (66.7% vs 39.6%, P = 0.001) and males (87.5% vs 48.4%, P < 0.001) than the no-synchronous group. The tumor diameter, mitotic index, and National Institutes of Health degree were also significantly different between the 2 groups (all P < 0.05). The 5-year disease-free survival and disease-specific survival rates of synchronous group were significantly lower than those of no-synchronous group (54.9% vs 93.5%, P < 0.001; 37.9% vs 89.9%, P < 0.001, respectively). However, the 5-year overall survival rates between synchronous and gastric cancer groups were comparable (37.9% vs 57.6%, P = 0.474).The coexistence of gastric GIST and gastric cancer was common in elder male patients. The synchronous GIST was common in low-risk category. The prognosis of gastric GIST with synchronous gastric cancer was worse than that of primary-single gastric GIST, but was comparable with primary-single gastric cancer.

  16. Life-threatening bleeding of a duodenal gastrointestinal stromal tumor in a teenager: a rare case report

    PubMed Central

    Valli, Piero V.; Valli, Carlo; Pfammatter, Thomas; Bauerfeind, Peter

    2016-01-01

    Duodenal gastrointestinal stromal tumors (GIST) are per se infrequent and are exceptional in children or young adults. So far, only 2 cases of pediatric duodenal GISTs have been published. Here we report on the case of a 19-year-old female patient who was admitted in hemorrhagic shock due to arterial bleeding of a duodenal GIST located in immediate proximity to the major duodenal papilla. After several attempts of endoscopic hemostasis failed, the tumor bleeding was controlled with a second coil embolization of the pancreaticoduodenal arcades. PMID:27995183

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

    PubMed Central

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

    2016-01-01

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

  18. Severe Imatinib-Associated Skin Rash in Gastrointestinal Stromal Tumor Patients: Management and Clinical Implications

    PubMed Central

    Park, Sook Ryun; Ryu, Min-Hee; Ryoo, Baek-Yeol; Beck, Mo Youl; Lee, In Soon; Choi, Mi Jung; Lee, Mi Woo; Kang, Yoon-Koo

    2016-01-01

    Purpose This study evaluated the incidence of imatinib-associated skin rash, the interventional outcomes of severe rash, and impact of severe rash on the outcomes of imatinib treatment in gastrointestinal stromal tumor (GIST) patients. Materials and Methods A total of 620 patients were administered adjuvant or palliative imatinib for GIST at Asan Medical Center between January 2000 and July 2012. This analysis focused on a group of 42 patients who developed a severe rash requiring major interventions, defined as dose interruption or reduction of imatinib or systemic steroid use. Results Of the 620 patients treated with imatinib, 148 patients (23.9%) developed an imatinib-associated skin rash; 42 patients (6.8%) developed a severe rash requiring major intervention. Of these, 28 patients (66.8%) successfully continued imatinib with interventions. Serial blood eosinophil levels during imatinib treatment were associated with skin rash and severity. A significant association was observed between successful intervention and blood eosinophil level at the time of intervention initiation. In metastatic settings, patients with severe rash requiring major interventions tended to show poorer progression-free survival than patients who did not require major intervention and patients with no rash, although this finding was not statistically significant (p=0.326). Conclusion By aggressive treatment of severe rash through modification of imatinib dose or use of systemic steroid, the majority of patients can continue on imatinib. In particular, imatinib dose intensity can be maintained with use of systemic steroid. Measuring the blood eosinophil levels may be helpful in guiding the management plan for skin rash regarding the intensity and duration of interventions. PMID:26323636

  19. Transcriptomic reappraisal identifies MGLL overexpression as an unfavorable prognosticator in primary gastrointestinal stromal tumors

    PubMed Central

    Liu, Ting-Ting; Chen, Ko-Chin; Chen, Yen-Yang; Fang, Fu-Min; Li, Shau-Hsuan; Chen, Tzu-Ju; Yu, Shih-Chen; Lan, Jui; Huang, Hsuan-Ying

    2016-01-01

    The role of deregulated cellular metabolism, particularly lipid metabolism, in gastrointestinal stromal tumors (GISTs) remains unclear. Through data mining of published transcriptomes, we examined lipid metabolism-regulating drivers differentially upregulated in high-risk cases and identified monoglyceride lipase (MGLL) as the top-ranking candidate involved in GIST progression. MGLL expression status was examined in three GIST cell lines and two independent sets of primary localized GISTs. MGLL mRNA abundance and immunoexpression was determined in 70 cases through the QuantiGene assay and H-scoring on whole sections, respectively. H-scoring was extended to another cohort for evaluating MGLL immunoexpression on tissue microarrays, yielding 350 informative cases, with KIT/PDGFRA mutation genotypes noted in 213 of them. Both imatinib-sensitive (GIST882) and -resistant (GIST48 and GIST430) cell lines exhibited increased MGLL expression. MGLL mRNA levels significantly increased from adjacent normal tissue to the non-high-risk group (p = 0.030) and from the non-high-risk group to high-risk GISTs (p = 0.012), and were associated with immunoexpression levels (p < 0.001, r = 0.536). MGLL overexpression was associated with the nongastric location (p = 0.022) and increased size (p = 0.017), and was strongly related to mitosis and risk levels defined by NIH and NCCN criteria (all p ≤ 0.001). Univariately, MGLL overexpression was strongly predictive of poorer disease-free and overall survival (both p < 0.001), which remained prognostically independent for both endpoints, along with higher risk levels. Conclusively, MGLL is a lipid metabolic enzyme causatively implicated in GIST progression given its association with unfavorable clincopathological factors and independent negative prognostic effects. PMID:27366945

  20. Oncogenic signaling by Kit tyrosine kinase occurs selectively on the Golgi apparatus in gastrointestinal stromal tumors.

    PubMed

    Obata, Y; Horikawa, K; Takahashi, T; Akieda, Y; Tsujimoto, M; Fletcher, J A; Esumi, H; Nishida, T; Abe, R

    2017-02-13

    Gastrointestinal stromal tumors (GISTs) are caused by gain-of-function mutations in the Kit receptor tyrosine kinase. Most primary GIST patients respond to the Kit inhibitor imatinib, but this drug often becomes ineffective because of secondary mutations in the Kit kinase domain. The characteristic intracellular accumulation of imatinib-sensitive and -resistant Kit protein is well documented, but its relationship to oncogenic signaling remains unknown. Here, we show that in cancer tissue from primary GIST patients as well as in cell lines, mutant Kit accumulates on the Golgi apparatus, whereas normal Kit localizes to the plasma membrane (PM). In imatinib-resistant GIST with a secondary Kit mutation, Kit localizes predominantly on the Golgi apparatus. Both imatinib-sensitive and imatinib-resistant Kit (Kit(mut)) become fully auto-phosphorylated only on the Golgi and only if in a complex-glycosylated form. Kit(mut) accumulates on the Golgi during the early secretory pathway, but not after endocytosis. The aberrant kinase activity of Kit(mut) prevents its export from the Golgi to the PM. Furthermore, Kit(mut) on the Golgi signals and activates the phosphatidylinositol 3-kinase-Akt (PI3K-Akt) pathway, signal transducer and activator of transcription 5 (STAT5), and the Mek-Erk pathway. Blocking the biosynthetic transport of Kit(mut) to the Golgi from the endoplasmic reticulum inhibits oncogenic signaling. PM localization of Kit(mut) is not required for its signaling. Activation of Src-family tyrosine kinases on the Golgi is essential for oncogenic Kit signaling. These results suggest that the Golgi apparatus serves as a platform for oncogenic Kit signaling. Our study demonstrates that Kit(mut)'s pathogenicity is related to its mis-localization, and may offer a new strategy for treating imatinib-resistant GISTs.Oncogene advance online publication, 13 February 2017; doi:10.1038/onc.2016.519.

  1. Dysregulated expression of Snail and E-cadherin correlates with gastrointestinal stromal tumor metastasis.

    PubMed

    Liu, Sheng; Liao, Guoqing; Ding, Jie; Ye, Ke; Zhang, Yi; Zeng, Liang; Chen, Senlin

    2014-09-01

    Snail, a zinc finger structure transcription inhibitory factor, has been reported to play an important role in the metastatic progression of several types of cancer. The aim of the study was to identify potential biomarkers for metastasis in gastrointestinal stromal tumors (GISTs) by examining the expression levels of Snail, E-cadherin, and Vimentin in GISTs and investigate their clinical significance. The protein expression of Snail, E-cadherin, and Vimentin in 74 GIST specimens was detected by immunohistochemical analysis, and the correlation between expression levels and clinicopathological data was analyzed. Snail, E-cadherin, and Vimentin were positively expressed in 51.4% (38/74), 32.4% (24/74), and 68.9% (51/74) of GIST tissue samples, respectively. Snail protein expression was significantly higher in GISTs with distant metastasis compared with GISTs without distant metastasis (P<0.05). E-cadherin expression level was significantly lower in cases of GIST with distant metastasis compared with those without distant metastasis (P<0.05), whereas the expression level of Vimentin did not significantly change according to clinical and pathological characteristics (all P>0.05). Snail expression was significantly negatively correlated with E-cadherin expression (r's=-0.276, P=0.017) but not with Vimentin expression (r's=0.041, P=0.728) in GISTs. High Snail expression and low E-cadherin expression were significantly correlated with metastasis in GISTs, and Snail, because of positive correlation, is potentially a biomarker of GIST with distant metastasis.

  2. Defects in succinate dehydrogenase in gastrointestinal stromal tumors lacking KIT and PDGFRA mutations

    PubMed Central

    Janeway, Katherine A.; Kim, Su Young; Lodish, Maya; Nosé, Vânia; Rustin, Pierre; Gaal, José; Dahia, Patricia L. M.; Liegl, Bernadette; Ball, Evan R.; Raygada, Margarita; Lai, Angela H.; Kelly, Lorna; Hornick, Jason L.; O'Sullivan, Maureen; de Krijger, Ronald R.; Dinjens, Winand N. M.; Demetri, George D.; Antonescu, Cristina R.; Fletcher, Jonathan A.; Helman, Lee; Stratakis, Constantine A.

    2011-01-01

    Carney-Stratakis syndrome, an inherited condition predisposing affected individuals to gastrointestinal stromal tumor (GIST) and paraganglioma, is caused by germline mutations in succinate dehydrogenase (SDH) subunits B, C, or D, leading to dysfunction of complex II of the electron transport chain. We evaluated the role of defective cellular respiration in sporadic GIST lacking mutations in KIT or PDGFRA (WT). Thirty-four patients with WT GIST without a personal or family history of paraganglioma were tested for SDH germline mutations. WT GISTs lacking demonstrable SDH genetic inactivation were evaluated for SDHB expression by immunohistochemistry and Western blotting and for complex II activity. For comparison, SDHB expression was also determined in KIT mutant and neurofibromatosis-1–associated GIST, and complex II activity was also measured in SDH-deficient paraganglioma and KIT mutant GIST; 4 of 34 patients (12%) with WT GIST without a personal or family history of paraganglioma had germline mutations in SDHB or SDHC. WT GISTs lacking somatic mutations or deletions in SDH subunits had either complete loss of or substantial reduction in SDHB protein expression, whereas most KIT mutant GISTs had strong SDHB expression. Complex II activity was substantially decreased in WT GISTs. WT GISTs, particularly those in younger patients, have defects in SDH mitochondrial complex II, and in a subset of these patients, GIST seems to arise from germline-inactivating SDH mutations. Testing for germline mutations in SDH is recommended in patients with WT GIST. These findings highlight a potential central role of SDH dysregulation in WT GIST oncogenesis. PMID:21173220

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

    PubMed

    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.

  4. Clinicopathologic study of 275 cases of gastrointestinal stromal tumors: the experience at 3 large medical centers in Mexico.

    PubMed

    Alvarado-Cabrero, Isabel; Vázquez, Gonzálo; Sierra Santiesteban, Francisca I; Hernández-Hernández, Dulce Ma; Pompa, Angel Zavala

    2007-02-01

    It is important to distinguish gastrointestinal (GI) stromal tumors (GISTs) from other GI mesenchymal tumors (GIMTs) because of the availability of molecular-targeted therapy for GISTs. The aim of the study was to reclassify GIMTs and to determine the clinicopathologic features of GISTs in Mexico. Cases of GIMT identified from the database of 3 large diagnostic centers in Mexico between 1995 and 2004 were reclassified according to current criteria. Hematoxylin and eosin-stained sections and clinical histories were reviewed, and immunohistochemistry was performed using anti-CD117, CD34, smooth muscle actin, and S-100 protein. A total of 275 GISTs were identified. The tumors were located in the stomach (40%), small intestine (35%), colorectum (12%), abdominal cavity (11%), and esophagus (2%). There were equal numbers of men and women with a mean age at diagnosis of 61 years. The tumors ranged in size from 3.5 to 34 cm (mean, 9.1 cm); 95 tumors (34%) were larger than 10 cm. Colorectal and omental tumors were the largest. The cell types included pure spindle (68%), pure epithelioid (16%), and mixed epithelioid/spindle (14%). Whereas 17.8% of tumors were regarded as low risk, 43% of tumors were in the high-risk category. CD117 positivity was detected in most of the tumors (96%). In addition to CD117, 255 cases (92%) were positive for CD34, 82 cases (32%) were positive for smooth muscle actin, and 13 cases (4.7%) were positive for desmin. Gastrointestinal stromal tumors in Mexico have the same clinicopathologic and immunohistochemical features as those reported in other countries. It is not always easy to distinguish GISTs from other soft tissue lesions. The diagnosis can be difficult even for experienced pathologists.

  5. Gastric stromal tumor.

    PubMed

    Ovali, Gülgün Yilmaz; Tarhan, Serdar; Serter, Selim; Pabuşçu, Yüksel

    2005-06-01

    Gastric stromal tumors are rare neoplasms of the stomach. In this report we present a gastric stromal tumor with an exophytic growth pattern, and describe magnetic resonance imaging and endoscopic ultrasonography findings.

  6. A case of multiple gastrointestinal stromal tumors caused by a germline KIT gene mutation (p.Leu576Pro).

    PubMed

    Vale Rodrigues, Rita; Santos, Filipa; Pereira da Silva, João; Francisco, Inês; Claro, Isabel; Albuquerque, Cristina; Lemos, Maria Manuel; Limbert, Manuel; Dias Pereira, António

    2017-04-01

    Multiple gastrointestinal stromal tumors (GISTs) caused by germline KIT gene mutations are an extremely rare autosomal dominant disorder. We report a case of a 21-year-old woman who presented to the emergency department with a 2-week history of asthenia, palpitations and upper gastrointestinal bleeding. After further clinical evaluation one gastric and two small bowel GISTs were diagnosed, which were surgically resected after neoadjuvant therapy with Imatinib. Diffuse hyperplasia of the interstitial cells of Cajal was also seen in the background gastric and small intestinal walls. Somatic mutational analysis of the KIT gene revealed a substitution at codon 576 in exon 11 (p.Leu576Pro) in all tumors and normal ileal mucosa. The germline nature of this mutation was confirmed by mutation analysis in peripheral blood leukocytes. However, she had no familial history of GISTs and her parents did not carry the respective germline mutation.

  7. Gastrointestinal stromal tumors (GIST): a rare entity, a tumor model for personalized therapy, and yet ten different molecular subtypes.

    PubMed

    Blay, Jean-Yves; Le Cesne, Axel; Cassier, Philippe A; Ray-Coquard, Isabelle L

    2012-05-01

    Gastrointestinal stromal tumors (GIST) are the most frequent sarcoma and were recognized as distinct molecular entities in 1998. Following the identification of driving molecular alterations in KIT, imatinib was rapidly introduced for the treatment of GIST, and became the paradigm of molecularly targeted therapies for solid tumors. While surgery was the only known effective treatment in 1998, two drugs are approved by the FDA and EMA in 2012 for the treatment of localized and advanced forms of this disease. Imatinib has been shown to provide a high level of clinical efficacy in patients with advanced GIST, a median progression-free survival (PFS) of 2 years and median overall survival close to 5 years, with 20% patients progression-free after 10 years of treatment. Imatinib has also been proven to improve overall survival and reduce the risk of relapse in localized GIST at high risk for relapse after resection. Sunitinib is indicated in advanced GIST after failure of imatinib, and provided a median PFS close to 6 months after imatinib failure. However, there is an important variability in the molecular and genetic characteristics that drive the pathogenesis of GIST, allowing thus for the identification of distinct molecular subtypes of GIST with different prognosis and sensitivity to the targeted treatments. Different strategies are now recommended in these different molecular subtypes of GIST which must be recognized as different entities regarding sensitivity to tyrosine kinase inhibitors and treatment decisions. This fragmentation of a yet recently recognized disease entity illustrates to strong trend of fragmentation in nosology of cancers, even in rare tumors such as GIST. For this aspect also, GIST is again a paradigmatic model for oncology, as many tumors with a higher prevalence will be fragmented in different molecular subsets and are going to become rare disease in the years to come.

  8. Gastrointestinal stromal tumor as entry port for S. intermedius causing bacteremia and multiple liver abscesses. Case report and review of literature.

    PubMed

    Benou, C; Walter, B M; Schlitter, M A; Wilhelm, D; Neu, B; Schmid, R M

    2016-03-01

    We report a case of a previously healthy 52-year-old man who presented with fever and liver lesions suspicious for metastatic disease, which proved subsequently to be abscesses. Further workup revealed a gastrointestinal stromal tumor (GIST) in the gastric corpus as entry port to Streptococcus intermedius-associated bacteremia and liver abscesses. After antibiotic treatment and surgical resection of the tumor, the patient recovered well. This unusual case indicates that gastrointestinal stromal tumors can remain undetected until they cause a life threatening infection. A review of recent literature pertaining to GIST and liver abscesses follows.

  9. First Case Report of a Sporadic Adrenocortical Carcinoma With Gastric Metastasis and a Synchronous Gastrointestinal Stromal Tumor of the Stomach.

    PubMed

    Kovecsi, Attila; Jung, Ioan; Bara, Tivadar; Bara, Tivadar; Azamfirei, Leonard; Kovacs, Zsolt; Gurzu, Simona

    2015-09-01

    Adrenocortical carcinoma is a rare tumor with high aggresivity that can associate systemic metastases. A 71-year-old man was hospitalized for gastric cancer. The abdominal computed tomography also revealed a tumor above the right kidney. Total gastrectomy and right adrenalectomy were performed. The encapsulated tumor of the adrenal gland weighed 560 grams and presented diffuse tumor architecture under microscope, with capsular, sinusoidal, and vascular invasion. The large tumor cells had a polygonal shape, with slight basophilic, eosinophilic, or vacuolated cytoplasm, pleomorphic nuclei, and a high mitotic rate. In the stomach, the protruded tumor was covered by normal mucosa; under microscope, the tumor cells were observed only in the submucosal layer. In primary adrenal tumor and gastric metastasis the tumor cells were marked by vimentin, inhibin, synaptophysin, neuron-specific enolase, and calretinin. Based on these criteria, the diagnosis of adrenocortical carcinoma (ACC) with gastric metastasis and no lymph node metastases was established. A synchronous 10 × 10-mm-sized gastrointestinal stromal tumor (GIST) of the stomach, without mitoses, was also identified. So far, as we know, this is the 15th case of ever reported synchronous/metachronous sporadic ACCs; the ACC-related gastric metastases either synchronous ACC and GIST, has not been reported in the literature previously.

  10. Gastrointestinal stromal tumor with a PDGFRA mutation masquerading as gastric plexiform fibromyxoma: A comparative clinicopathological study of two cases

    PubMed Central

    Zhou, Jun; Xu, Jingjing; Jiang, Guozhong; Ma, Yihui; Qi, Jingwen; Li, Wencai; Zhang, Dandan

    2017-01-01

    Gastric plexiform fibromyxoma (PF) is a rare mesenchymal tumor with a histologically distinctive multinodular pattern, dissimilar to conventional gastrointestinal stromal tumor (GIST). The current study presents one case of gastric PF, and one case of GIST with a platelet-derived growth factor receptor α (PDGFRA) mutation mimicking PF, and discusses their differential diagnoses. The two patients were a 51-year-old male with PF and a 47-year-old female with GIST, each of whom presented with an occupying lesion in the gastric antrum. Histologically, the two cases shared a rare and approximately unanimous morphological pattern of a prominent multinodular and plexiform figuration in the gastric wall, including mucoid matrix, short spindle cells and small caliber vascular elements, and areas of stromal tumor cells exhibited an epithelioid appearance. Immunohistochemistry revealed that the PF tumor cells were positive for smooth muscle actin (SMA), but negative for mast/stem cell growth factor receptor (KIT), GIST-1 (DOG1), cluster of differentiation (CD) 34, S-100, desmin and cytokeratin AE1/AE3. The case of GIST expressed KIT and DOG1, but was negative for SMA, CD34, S-100, desmin and AE1/AE3. In addition, the GIST case, which was observed to harbor a D842V mutation in exon 18 of PDGFRA, was demonstrated to be genetically distinct from PF. The cases presented in the current study were uncommon in that GIST exhibited a plexiform appearance that mimicked the histology of the rare PF tumor; therefore, GIST must be considered and discounted first when determining a differential diagnosis for a gastrointestinal mesenchymal neoplasm. PMID:28356974

  11. Advances in preclinical therapeutics development using small animal imaging and molecular analyses: the gastrointestinal stromal tumors model.

    PubMed

    Pantaleo, M A; Landuzzi, L; Nicoletti, G; Nanni, C; Boschi, S; Piazzi, G; Santini, D; Di Battista, M; Castellucci, P; Lodi, F; Fanti, S; Lollini, P-L; Biasco, G

    2009-09-01

    The large use of target therapies in the treatment of gastrointestinal stromal tumors (GISTs) highlighted the urgency to integrate new molecular imaging technologies, to develop new criteria for tumor response evaluation and to reach a more comprehensive definition of the molecular target. These aspects, which come from clinical experiences, are not considered enough in preclinical research studies which aim to evaluate the efficacy of new drugs or new combination of drugs with molecular target. We developed a xenograft animal model GIST882 using nude mice. We evaluated both the molecular and functional characterization of the tumor mass. The mutational analysis of KIT receptor of the GIST882 cell lines and tumor mass showed a mutation on exon 13 that was still present after in vivo cell growth. The glucose metabolism and cell proliferation was evaluated with a small animal PET using both FDG and FLT. The experimental development of new therapies for GIST treatment requires sophisticated animal models in order to represent the tumor molecular heterogeneity already demonstrated in the clinical setting and in order to evaluate the efficacy of the treatment also considering the inhibition of tumor metabolism, and not only considering the change in size of tumors. This approach of cancer research on GISTs is crucial and essential for innovative perspectives that could cross over to other types of cancer.

  12. Splenosis in gastric fundus mimicking gastrointestinal stromal tumor: a report of two cases and review of the literature.

    PubMed

    Li, Bin; Huang, Ya; Chao, Baoting; Zhao, Qi; Hao, Jinghua; Qin, Chengyong; Xu, Hongwei

    2015-01-01

    Splenosis refers to heterotopic autotransplantation and implantation of splenic tissue following splenic trauma or surgery. Splenosis in gastric fundus is rare and difficult to diagnose, since splenosis has similar manifestation with gastrointestinal stromal tumor (GIST) under routine endoscopy examination. In this report, we present two quite rare case of splenosis. Both of their pre-operative diagnose under endoscopic ultrasonography was considered as GIST. Finally, one in the abdominal cavity, adhering closely to the gastric fundus, measuring 20 mm × 15 mm, was resected by surgical operation, and one in the gastric fundus, measuring 20 mm × 20 mm, was resected by endoscopic surgery. The precise diagnosis of splenosis was distinct by post-operative histopathologic examination. In addition, we also made a mini review of previously published articles, in order to provide indication to solve future doubts in diagnosing and treating splenosis.

  13. Comparison of Gene Expression Profile Between Tumor Tissue and Adjacent Non-tumor Tissue in Patients with Gastric Gastrointestinal Stromal Tumor (GIST).

    PubMed

    Kou, Youwei; Zhao, Ying; Bao, Chenhui; Wang, Qiang

    2015-06-01

    Gastrointestinal stromal tumors (GISTs) are defined as spindle cell and/or epithelioid tumors originated from interstitial Cajal cells or precursors in the digestive tract. This study was conducted to identify genes differing in expression between the gastric tumors and the adjacent non-cancerous mucosas in patients with primary gastric GIST. The gene expression profile was determined by using oligonucleotide-based DNA microarrays and further validated by quantitative real-time PCR. The Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis was performed to predict signaling pathways involved in gastric GIST. Our data showed that the expression levels of 957 genes (RAB39B, member RAS oncogene family; VCAN, versican; etc.) were higher and that of 526 genes (CXCL14, chemokine C-X-C motif ligand 14; MTUS1, microtubule-associated tumor suppressor 1; etc.) were lower in the gastric tumor tissues as compared with normal gastric tissues. Results from KEGG pathway analysis revealed that the differentially expressed genes were enriched into 16 signaling transduction pathways, including Hedeghog and Wnt signaling pathways. Our study may provide basis for identification of novel biomarkers associated with primary gastric GIST pathogenesis and for exploration of underlying mechanisms involved in this gastric sarcoma.

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

    PubMed Central

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

    2016-01-01

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

  15. Gastrointestinal stromal tumor and other primary metachronous or synchronous neoplasms as a suspicion criterion for syndromic setting.

    PubMed

    Ponti, Giovanni; Luppi, Gabriele; Martorana, Davide; Rossi, Giulio; Losi, Lorena; Bertolini, Federica; Sartori, Giuliana; Pellacani, Giovanni; Seidenari, Stefania; Boni, Elisa; Neri, Tauro Maria; Silini, Enrico; Tamburini, Elisa; Maiorana, Antonio; Conte, Pier Franco

    2010-02-01

    Gastrointestinal stromal tumors (GISTs) may be sporadic or inherited. Although KIT and PDGFRA activating mutations are the oncogenic mechanisms in most sporadic and inherited GISTs, a small subset of GISTs are negative for both. Besides the classical Familial GIST Syndrome, GIST can occur as part of multi-neoplastic disease. The present study was designed to analyze the synchronous and metachronous tumors developed among GIST patients assessed by our institution for GIST Syndrome setting recognition. Patients (n=141) with primary GIST (77 men and 64 women) were recruited between 1988 and 2007 and their clinical and pathological records were reviewed. Mutation analysis of KIT, PDGFRA, NF1 and MMR genes was performed on somatic and peripheral blood DNA. GISTs occurred associated with other primary malignancies in 46 of 141 (32.6%) patients. The most common neoplasms were gastrointestinal and genitourinary. A novel exon 6 germline large deletion of NF1 was identified in the NF1/GIST kindred. The development of GIST associated with other neoplasms is common and diagnosis of peculiar benign associated-neoplasms warrants the search for familial cancer susceptibility. In particular, syndromic or familial settings have to be suspected in the presence of neurofibroma or lung chordoma in C-KIT and PDGFRA negative GIST patients.

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

    PubMed Central

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

    2015-01-01

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

  17. A Foregut Duplication Cyst of the Stomach in Association with a Gastrointestinal Stromal Tumor and a Leiomyoma: A Case Report

    PubMed Central

    Gagné, Andréanne; Sazonova, Olga; Marceau, Simon; Périgny, Martine

    2016-01-01

    Objectives. Duplication cysts are rare benign lesions usually arising in the gastrointestinal tract. We report a case of a 52-year-old woman with an incidental gastric mass found on computed tomography during a pregraft workup for a familial cardiomyopathy. Methods. The mass was completely excised by partial gastrectomy and gross examination revealed a cystic lesion containing two small solid nodules in its wall. Microscopic evaluation and immunohistochemistry study were performed to further characterize the cyst and the nodules. A comprehensive literature review of the NCBI database PubMed was also carried out. Results. While the cyst was diagnosed as a foregut duplication cyst, the solid nodules proved to be concomitant gastrointestinal stromal tumor (GIST) and leiomyoma. Both morphologic features and immunohistochemistry stains, including CD117, smooth muscle actin, and CD34 supported the diagnosis. Clinical course was benign and the patient had no clinical evidence of relapse ten months following the surgical procedure. The literature search did not reveal any other published case of a foregut duplication cyst presenting in combination with a GIST and a leiomyoma. Conclusions. To our knowledge, this is the first case of a composite lesion comprising a foregut duplication cyst of the stomach along with a leiomyoma and a GIST. PMID:28097030

  18. Comparison of Different Risk Classification Systems in 558 Patients with Gastrointestinal Stromal Tumors after R0-Resection

    PubMed Central

    Schmieder, Michael; Henne-Bruns, Doris; Mayer, Benjamin; Knippschild, Uwe; Rolke, Claudia; Schwab, Matthias; Kramer, Klaus

    2016-01-01

    Background: Due to adjuvant treatment concepts for patients with R0-resected gastrointestinal stromal tumors (GIST), a reproducible and reliable risk classification system proved of utmost importance for optimal treatment of patients and prediction of prognosis. The aim of this study was to reevaluate the impact of five widely-applied and well-established GIST risk classification systems (i.e., scores by Fletcher, Miettinen, Huang, Joensuu, and TNM classification) on a series of 558 GIST patients with long-term follow-up after R0 resection. Methods: Tumor size, mitotic count and site were used in variable combination to predict high- and low risk patients by the use of the five risk classification models. For survival analyses disease-specific survival, disease-free survival and overall-survival were investigated. Patients with initial metastatic disease or incompletely resectable tumors were excluded. Results: All GIST classification models distinguished well between patients with high-risk and low-risk tumors and none of the five risk systems was superior to predict patient outcome. The models showed significant heterogeneity. There was no significant difference between the different risk-groups regarding overall-survival. Subdivision of GIST patients with very low- and low-risk appeared to be negligible. Conclusions: Currently applied GIST risk classification systems are comparable to predict high- or low-risk patients with initial non-metastatic and completely resected GIST. However, the heterogeneity of the high-risk group and the absence of differences in overall survival indicate the need for more precise tumor- and patient-related criteria for better stratification of GIST and identification of patients who would benefit best from adjuvant tyrosine kinase inhibitor therapy. PMID:28082898

  19. Novel V600E BRAF mutations in imatinib-naive and imatinib-resistant gastrointestinal stromal tumors.

    PubMed

    Agaram, Narasimhan P; Wong, Grace C; Guo, Tianhua; Maki, Robert G; Singer, Samuel; Dematteo, Ronald P; Besmer, Peter; Antonescu, Cristina R

    2008-10-01

    BRAF and NRAS are commonly mutated in cancer and represent the most frequent genetic events in malignant melanoma. More recently, a subset of melanomas was shown to overexpress KIT and harbor KIT mutations. Although most gastrointestinal stromal tumors (GISTs) exhibit activating mutations in either KIT or PDGFRA, about 10% of the cases lack mutations in these genes. It is our hypothesis following the melanoma model that mutations in BRAF or NRAS may play a role in wild-type GIST pathogenesis. Alterations in RAS/MEK/ERK pathway may also be involved in development of imatinib resistance in GIST, particularly in tumors lacking secondary KIT or PDGFRA mutations. Imatinib-naive wild-type GISTs from 61 patients, including 15 children and 28 imatinib-resistant tumors without secondary KIT mutations were analyzed. Screening for hot spots mutations in BRAF (exons 11 and 15) and NRAS (exons 2 and 3) was performed. A BRAF exon 15 V600E was identified in 3 of 61 GIST patients, who shared similar clinical features, being 49- to 55-years-old females and having their tumors located in the small bowel. The tumors were strongly KIT immunoreactive and had a high risk of malignancy. An identical V600E BRAF mutation was also identified in one of 28 imatinib resistant GIST lacking a defined mechanism of drug resistance. In conclusion, we identified a primary BRAF V600E mutations in 7% of adult GIST patients, lacking KIT/PDGFRA mutations. The BRAF-mutated GISTs show predilection for small bowel location and high risk of malignancy. A secondary V600E BRAF mutation could represent an alternative mechanism of imatinib resistance. Kinase inhibitors targeting BRAF may be effective therapeutic options in this molecular GIST subset.

  20. Is surgery mandatory in locally advanced gastrointestinal stromal tumors after imatinib? A case report and literature review

    PubMed Central

    Congedo, Teresa; Ricci, Riccardo; Martini, Maurizio; Di Noia, Vincenzo; Di Dio, Carmela; Quirino, Michela; Barone, Carlo; Cassano, Alessandra

    2017-01-01

    Oesophageal gastrointestinal stromal tumors (GISTs) are rare neoplasms (about 2% of all GISTs); radical surgery is the standard treatment of all GISTs but in case of locally advanced and unresectable disease no clear treatment guide lines are available. Studies including neoadjuvant imatinib mesylate (IM) are relatively recent, includes small sample size of heterogeneous patients and do not report a standardized duration of neoadjuvant treatment. The main question still remains whether surgery after neoadjuvant IM gives a survival benefit in locally advanced disease. A 46-year-old man with locally advanced unresectable oesophageal GIST harboring KIT exon 11 mutation was treated in our institution for 12 months with neoadjuvant IM; a reduction of 83% of tumor volume was obtained in 9-month of neoadjuvant IM, but in the last 3 months no further response was seen. After neoadjuvant therapy, patient underwent radical surgery and adjuvant IM, which is still ongoing. Since no definitive data are available about survival benefit of surgery after neoadjuvant IM in locally advanced GISTs, a careful balance between morbidity and mortality derived from surgery should be considered and more studies are needed to better define the utility and the optimal duration of neoadjuvant treatment. PMID:28280629

  1. Frequence, Spectrum and Prognostic Impact of Additional Malignancies in Patients With Gastrointestinal Stromal Tumors1234

    PubMed Central

    Kramer, K.; Wolf, S.; Mayer, B.; Schmidt, S.A.; Agaimy, A.; Henne-Bruns, D.; Knippschild, U.; Schwab, M.; Schmieder, M.

    2015-01-01

    Currently available data on prognostic implication of additional neoplasms in GIST miss comprehensive information on patient outcome with regard to overall or disease specific and disease free survival. Registry data of GIST patients with and without additional neoplasm were compared in retrospective case series. We investigated a total of 836 patients from the multi-center Ulmer GIST registry. Additionally, a second cohort encompassing 143 consecutively recruited patients of a single oncology center were analyzed. The frequency of additional malignant neoplasms in GIST patients was 31.9% and 42.0% in both cohorts with a mean follow-up time of 54 and 65 months (median 48 and 60 months), respectively. The spectrum of additional neoplasms in both cohorts encompasses gastrointestinal tumors (43.5%), uro-genital and breast cancers (34.1%), hematological malignancies (7.3%), skin cancer (7.3%) and others. Additional neoplasms have had a significant impact on patient outcome. The five year overall survival in GIST with additional malignant neoplasms (n = 267) was 62.8% compared to 83.4% in patients without other tumors (n = 569) (P < .001, HR=0.397, 95% CI: 0.298-0.530). Five-year disease specific survival was not different between both groups (90.8% versus 90.9%). 34.2% of all deaths (n = 66 of n = 193) were GIST-related. The presented data suggest a close association between the duration of follow-up and the rate of additional malignancies in GIST patients. Moreover the data indicate a strong impact of additional malignant neoplasms in GIST on patient outcome. A comprehensive follow-up strategy of GIST patients appears to be warranted. PMID:25622906

  2. Hedgehog pathway dysregulation contributes to the pathogenesis of human gastrointestinal stromal tumors via GLI-mediated activation of KIT expression

    PubMed Central

    Burgoyne, Adam M.; Leonard, Stephanie Y.; Gao, Fei; Chan, Jonathan C.; Shi, Eileen; Chmielecki, Juliann; Morosini, Deborah; Wang, Kai; Ross, Jeffrey S.; Kendrick, Michael L.; Bardsley, Michael R.; De Siena, Martina; Mao, Junhao; Harismendy, Olivier

    2016-01-01

    Gastrointestinal stromal tumors (GIST) arise within the interstitial cell of Cajal (ICC) lineage due to activating KIT/PDGFRA mutations. Both ICC and GIST possess primary cilia (PC), which coordinate PDGFRA and Hedgehog signaling, regulators of gastrointestinal mesenchymal development. Therefore, we hypothesized that Hedgehog signaling may be altered in human GIST and controls KIT expression. Quantitative RT-PCR, microarrays, and next generation sequencing were used to describe Hedgehog/PC-related genes in purified human ICC and GIST. Genetic and pharmacologic approaches were employed to investigate the effects of GLI manipulation on KIT expression and GIST cell viability. We report that Hedgehog pathway and PC components are expressed in ICC and GIST and subject to dysregulation during GIST oncogenesis, irrespective of KIT/PDGFRA mutation status. Using genomic profiling, 10.2% of 186 GIST studied had potentially deleterious genomic alterations in 5 Hedgehog-related genes analyzed, including in the PTCH1 tumor suppressor (1.6%). Expression of the predominantly repressive GLI isoform, GLI3, was inversely correlated with KIT mRNA levels in GIST cells and non-KIT/non-PDGFRA mutant GIST. Overexpression of the 83-kDa repressive form of GLI3 or small interfering RNA-mediated knockdown of the activating isoforms GLI1/2 reduced KIT mRNA. Treatment with GLI1/2 inhibitors, including arsenic trioxide, significantly increased GLI3 binding to the KIT promoter, decreased KIT expression, and reduced viability in imatinib-sensitive and imatinib-resistant GIST cells. These data offer new evidence that genes necessary for Hedgehog signaling and PC function in ICC are dysregulated in GIST. Hedgehog signaling activates KIT expression irrespective of mutation status, offering a novel approach to treat imatinib-resistant GIST. PMID:27793025

  3. The HSP90 Inhibitor, AT13387, Is Effective against Imatinib-Sensitive and -Resistant Gastrointestinal Stromal Tumor Models

    PubMed Central

    Smyth, Tomoko; Van Looy, Thomas; Curry, Jayne E.; Rodriguez-Lopez, Ana M.; Wozniak, Agnieszka; Zhu, Meijun; Donsky, Rachel; Morgan, Jennifer G.; Mayeda, Mark; Fletcher, Jonathan A.; Schöffski, Patrick; Lyons, John; Thompson, Neil T.; Wallis, Nicola G.

    2013-01-01

    The majority of gastrointestinal stromal tumors (GIST) are characterized by activating mutations of KIT, an HSP90 client protein. Further secondary resistance mutations within KIT limit clinical responses to tyrosine kinase inhibitors, such as imatinib. The dependence of KIT and its mutated forms on HSP90 suggests that HSP90 inhibition might be a valuable treatment option for GIST, which would be equally effective on imatinib-sensitive and -resistant clones. We investigated the activity of AT13387, a potent HSP90 inhibitor currently being evaluated in clinical trials, in both in vitro and in vivo GIST models. AT13387 inhibited the proliferation of imatinib-sensitive (GIST882, GIST-T1) and -resistant (GIST430, GIST48) cell lines, including those resistant to the geldanamycin analogue HSP90 inhibitor, 17-AAG. Treatment with AT13387 resulted in depletion of HSP90 client proteins, KIT and AKT, along with their phospho-forms in imatinib-sensitive and -resistant cell lines, irrespective of KIT mutation. KIT signaling was ablated, whereas HSP70, a marker of HSP90 inhibition, was induced. In vivo, antitumor activity of AT13387 was showed in both the imatinib-sensitive, GIST-PSW, xenograft model and a newly characterized imatinib-resistant, GIST430, xenograft model. Induction of HSP70, depletion of phospho-KIT and inhibition of KIT signaling were seen in tumors from both models after treatment with AT13387. A combination of imatinib and AT13387 treatment in the imatinib-resistant GIST430 model significantly enhanced tumor growth inhibition over either of the monotherapies. Importantly, the combination of AT13387 and imatinib was well tolerated. These results suggest AT13387 is an excellent candidate for clinical testing in GIST in combination with imatinib. PMID:22714264

  4. Microfluidic Deletion/Insertion Analysis for Rapid Screening of KIT and PDGFRA Mutations in CD117-Positive Gastrointestinal Stromal Tumors

    PubMed Central

    Zamò, Alberto; Bertolaso, Anna; Franceschetti, Ilaria; Weirich, Gregor; Capelli, Paola; Pecori, Sara; Chilosi, Marco; Hoefler, Heinz; Menestrina, Fabio; Scarpa, Aldo

    2007-01-01

    Gastrointestinal stromal tumors (GISTs) frequently harbor mutations in the KIT and PDGFRA genes, the presence and type of which correlate with the response to the kinase inhibitor imatinib mesylate. Because most GIST mutations are deletions/insertions, we used a microfluidic apparatus to detect these size variations in polymerase chain reaction-amplified DNA. This approach, termed microfluidic deletion/insertion analysis (MIDIA), identified mutations in 30 of 50 DNA samples from paraffin-embedded CD117-positive GISTs (60%), comprising 25 deletions and five insertions. Sequencing of 14 MIDIA-positive samples confirmed the deletions/insertions, including two 3-bp alterations. Sequencing of all 20 MIDIA-negative samples also showed highly consistent results with MIDIA because 10 cases were wild type and eight displayed a single base substitution in which detection by MIDIA was not expected. Sequencing also revealed a 3-bp deletion undetected by MIDIA, thus establishing the resolution limit of MIDIA at deletions/insertions ≥3 bp. Denaturing high-pressure liquid chromatography analysis confirmed all mutations detected by MIDIA and sequencing. We propose MIDIA as the first step in mutational screening of GIST because it allowed the detection of 75% of mutated cases (94% of deletions/insertions) in less than 30 minutes after polymerase chain reaction amplification and at a lower cost compared with denaturing high-pressure liquid chromatography and sequencing, which might then be used only for MIDIA-negative cases. PMID:17384206

  5. Opposing roles of KIT and ABL1 in the therapeutic response of gastrointestinal stromal tumor (GIST) cells to imatinib mesylate.

    PubMed

    Rausch, Jessica L; Boichuk, Sergei; Ali, Areej A; Patil, Sneha S; Liu, Lijun; Lee, Donna M; Brown, Matthew F; Makielski, Kathleen R; Liu, Ying; Taguchi, Takahiro; Kuan, Shih-Fan; Duensing, Anette

    2017-01-17

    Most gastrointestinal stromal tumors (GISTs) are caused by activating mutations of the KIT receptor tyrosine kinase. The small molecule inhibitor imatinib mesylate was initially developed to target the ABL1 kinase, which is constitutively activated through chromosomal translocation in BCR-ABL1-positive chronic myeloid leukemia. Because of cross-reactivity of imatinib against the KIT kinase, the drug is also successfully used for the treatment of GIST. Although inhibition of KIT clearly has a major role in the therapeutic response of GIST to imatinib, the contribution of concomitant inhibition of ABL in this context has never been explored. We show here that ABL1 is expressed in the majority of GISTs, including human GIST cell lines. Using siRNA-mediated knockdown, we demonstrate that depletion of KIT in conjunction with ABL1 - hence mimicking imatinib treatment - leads to reduced apoptosis induction and attenuated inhibition of cellular proliferation when compared to depletion of KIT alone. These results are explained by an increased activity of the AKT survival kinase, which is mediated by the cyclin-dependent kinase CDK2, likely through direct phosphorylation. Our results highlight that distinct inhibitory properties of targeted agents can impede antitumor effects and hence provide insights for rational drug development. Novel KIT-targeted agents to treat GIST should therefore comprise an increased specificity for KIT while at the same time displaying a reduced ability to inhibit ABL1.

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

    PubMed

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

    2016-07-21

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

  7. Autophagy is involved in endogenous and NVP-AUY922-induced KIT degradation in gastrointestinal stromal tumors

    PubMed Central

    Hsueh, Yuan-Shuo; Yen, Chueh-Chuan; Shih, Neng-Yao; Chiang, Nai-Jung; Li, Chien-Feng; Chen, Li-Tzong

    2013-01-01

    Gastrointestinal stromal tumor (GIST) is a prototype of mutant KIT oncogene-driven tumor. Prolonged tyrosine kinase inhibitor (TKI) treatment may result in a resistant phenotype through acquired secondary KIT mutation. Heat shock protein 90 (HSP90AA1) is a chaperone protein responsible for protein maturation and stability, and KIT is a known client protein of HSP90AA1. Inhibition of HSP90AA1 has been shown to destabilize KIT protein by enhancing its degradation via the proteasome-dependent pathway. In this study, we demonstrated that NVP-AUY922 (AUY922), a new class of HSP90AA1 inhibitor, is effective in inhibiting the growth of GIST cells expressing mutant KIT protein, the imatinib-sensitive GIST882 and imatinib-resistant GIST48 cells. The growth inhibition was accompanied with a sustained reduction of both total and phosphorylated KIT proteins and the induction of apoptosis in both cell lines. Surprisingly, AUY922-induced KIT reduction could be partially reversed by pharmacological inhibition of either autophagy or proteasome degradation pathway. The blockade of autophagy alone led to the accumulation of the KIT protein, highlighting the role of autophagy in endogenous KIT turnover. The involvement of autophagy in endogenous and AUY922-induced KIT protein turnover was further confirmed by the colocalization of KIT with MAP1LC3B-, acridine orange- or SQSTM1-labeled autophagosome, and by the accumulation of KIT in GIST cells by silencing either BECN1 or ATG5 to disrupt autophagosome activity. Therefore, the results not only highlight the potential application of AUY922 for the treatment of KIT-expressing GISTs, but also provide the first evidence for the involvement of autophagy in endogenous and HSP90AA1 inhibitor-induced KIT degradation. PMID:23196876

  8. Analysis of the amount of tissue sample necessary for mitotic count and Ki-67 index in gastrointestinal stromal tumor sampling.

    PubMed

    Kobara, Hideki; Mori, Hirohito; Rafiq, Kazi; Fujihara, Shintaro; Nishiyama, Noriko; Chiyo, Taiga; Matsunaga, Tae; Ayaki, Maki; Yachida, Tatsuo; Kato, Kiyohito; Kamada, Hideki; Fujita, Koji; Morishita, Asahiro; Oryu, Makoto; Tsutsui, Kunihiko; Iwama, Hisakazu; Kushida, Yoshio; Haba, Reiji; Masaki, Tsutomu

    2015-01-01

    There are no established opinions concerning whether the amount of tissue affects the accuracy of histological analyses in gastrointestinal stromal tumors (GISTs). The aim of the present study was to investigate the appropriate amount of tissue sample needed for mitotic count based on the risk classification of GISTs and the Ki-67 index using the following three methods: endoscopic ultrasound-guided fine-needle aspiration (FNA), a novel sampling method called tunneling bloc biopsy (TBB), and biopsy forceps followed by TBB (Bf). Forty-three samples (12 FNA, 17 TBB and 14 Bf) diagnosed as GISTs by immunohistological analysis were utilized. The major and minor axes and overlay area of one piece of specimen (OPS) from the three sampling methods were measured using digital imaging software and were analyzed comparatively regarding the acquisition of histological data. The mean major and minor axes (mm) and overlay areas (mm2) were in the order of TBB > Bf > FNA. The evaluable rates by mitotic count and Ki-67 were, respectively, 75% (9/12) and 83.3% (10/12) for FNA samples, 100% (17/17) and 100% (17/17) for TBB samples, and 100% (14/14) and 100% (14/14) for Bf samples (P>0.05). Three FNA samples were judged unevaluable due to too small specimens in overall diagnosis including mitotic count and Ki-67, calculating the cut-off value for the overlay area of OPS as 0.17 mm2. Comparing the concordance rates between the pre- and post-operative samples, TBB samples was significantly better than FNA (P<0.05). Conclusively, while the amounts of tissues obtained by TBB and Bf are unnecessary for the histological assessment of mitotic count and Ki-67 index, developments of the FNA method are needed to minimize sample error. Considering the technical aspects, as well as the size of the specimens, could help to guide therapeutic planning and improve diagnostic yield for GI subepithelial tumors.

  9. Antitumor effect of the tyrosine kinase inhibitor nilotinib on gastrointestinal stromal tumor (GIST) and imatinib-resistant GIST cells.

    PubMed

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

    2014-01-01

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

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed Central

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

    2015-01-01

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

  12. Immunohistochemical loss of succinate dehydrogenase subunit A (SDHA) in gastrointestinal stromal tumors (GISTs) signals SDHA germline mutation.

    PubMed

    Miettinen, Markku; Killian, Jonathan Keith; Wang, Zeng-Feng; Lasota, Jerzy; Lau, Christopher; Jones, Laura; Walker, Robert; Pineda, Marbin; Zhu, Yuelin Jack; Kim, Su Y; Helman, Lee; Meltzer, Paul

    2013-02-01

    A subset (7% to 10%) of gastric gastrointestinal stromal tumors (GISTs) is notable for the immunohistochemical loss of succinate dehydrogenase (SDH) subunit B (SDHB), which signals the loss of function of the SDH complex consisting of mitochondrial inner membrane proteins. These SDH-deficient GISTs are known to be KIT/PDGFRA wild type, and most patients affected by this subset of GISTs are young. Some of these patients have germline mutations of SDH subunit genes SDHB, SDHC, or SDHD, known as Carney-Stratakis syndrome when combined with paraganglioma. More recently, germline mutations in SDH subunit A gene (SDHA) have also been reported in few patients with KIT/PDGFRA wild-type GISTs. In this study we immunohistochemically examined 127 SDHB-negative and 556 SDHB-positive gastric GISTs and 261 SDHB-positive intestinal GISTs for SDHA expression using a mouse monoclonal antibody 2E3 (Abcam). Cases with available DNA were tested for SDHA, SDHB, SDHC, and SDHD gene mutations using a hybridization-based custom capture next-generation sequencing assay. A total of 36 SDHA-negative GISTs (28%) were found among 127 SDHB-negative gastric GISTs. No SDHB-positive GIST was SDHA negative. Among 7 SDHA-negative tumors analyzed, there were 7 SDHA mutants, most germline. A second hit indicating biallelic inactivation of SDHA was present in 6 of those cases. These patients had no other SDH subunit gene mutations. Among the 25 SDHA-positive, SDHB-negative GISTs analyzed, we identified 3 SDHA mutations (1 germline), and 11 SDHB, SDHC, or SDHD mutations (mostly germline), and 11 patients with no SDH mutations. Compared with patients with SDHA-positive GISTs, those with SDHA-negative GISTs had an older median age (34 vs. 21 y), lower female to male ratio (1.8 vs. 3.1) but similar mitotic counts and median tumor sizes, with a slow course of disease in most cases, despite a slightly higher rate of liver metastases. SDHA-negative GISTs comprise approximately 30% of SDHB

  13. Synchronous Occurrence of Diffuse Large B-cell Lymphoma of the Duodenum and Gastrointestinal Stromal Tumor of the Ileum in a Patient with Immune Thrombocytopenic Purpura

    PubMed Central

    Takahashi, Tohru; Maruyama, Yumiko; Saitoh, Mayuko; Itoh, Hideto; Yoshimoto, Mitsuru; Tsujisaki, Masayuki; Nakayama, Masato

    2016-01-01

    A 64 year-old woman with steroid-dependent immune thrombocytopenia developed anemia. Esophagogastroduodenoscopy revealed the presence of a tumor, which was diagnosed to be diffuse large B-cell lymphoma, in the second portion of the duodenum. 18F-fluorodeoxy glucose positron emission tomography showed an increased uptake mass in the pelvic cavity as well as in the duodenum. Though the duodenal tumor disappeared after 4 cycles of chemotherapy, the pelvic mass did not shrink in size. As a result, laparoscopic resection of the pelvic tumor was performed and the tumor was histologically diagnosed to be a gastrointestinal stromal tumor. Subsequently, the patient was treated with 2 more cycles of the chemotherapy. Eventually, thrombocytopenia completely resolved. PMID:27746431

  14. Atypical presentation of gastrointestinal stromal tumours-a case report.

    PubMed

    Raja, Kalpana; Dev, Bhawna; Santosham, Roy; Santhosh, Joseph

    2013-06-01

    Gastrointestinal stromal tumors (GISTs) are benign mesenchymal tumors of the gastrointestinal tract (GIT). Their clinical presentations are variable. We report a case of a 31-year-old man who presented with pain in the abdomen and vomiting. CT abdomen revealed a large exophytic mass in the epigastrium with enhancement pattern similar to hemangioma. No relationship of the mass could be made out with the adjacent structures on CT, histopathology proved it to be a GIST.

  15. Gastrointestinal Stromal Tumours: An Update

    PubMed Central

    Somerhausen, Nicolas De Saint Aubain

    1998-01-01

    Purpose. To study the evolution of concepts concerning gastrointestinal stromal tumours (GISTs) over 30 years. Discussion. GISTs have been, for more than 30 years, the subject of considerable controversy regarding their line of differentiation as well as the prediction of their behaviour. Furthermore, once they spread within the peritoneal cavity, they are extremely hard to control. The recent findings of c-Kit mutations and the immunohistochemical detection of the product of this gene, KIT or CD117, in the mainly non-myogenic subset of this family of tumours, has led to a reappraisal of this group of lesions, which, with some exceptions, is now thought to be derived from the interstitial cells of Cajal, and this has facilitated a clearer definition of their pathological spectrum. In this article, we review chronologically the evolution of the concept of GIST with the gradual application of electron microscopy, immunohistochemistry, DNA ploidy analysis. We discuss the impact of these techniques on the pathological assessment and clinical management of GISTs. PMID:18521245

  16. Skull metastasis from rectal gastrointestinal stromal tumours.

    PubMed

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

    2009-09-01

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

  17. Expression of neural cell adhesion molecule L1 (CD171) in neuroectodermal and other tumors. An immunohistochemical study of 5155 tumors and critical evaluation of CD171 prognostic value in gastrointestinal stromal tumors

    PubMed Central

    Inaguma, Shingo; Wang, Zengfeng; Lasota, Jerzy P.; Miettinen, Markku M.

    2016-01-01

    The neural cell adhesion molecule L1 (CD171) is a multidomain type 1 membrane glycoprotein of the immunoglobulin superfamily important in the nervous system development, kidney morphogenesis, and maintenance of the immune system. Recent studies reported CD171 expression being associated with adverse clinical outcome in different types of cancer and there has been a growing interest in targeting this cell membrane molecule on neoplastic cells by chimeric antigen receptor redirected T lymphocytes or specific antibodies. Nevertheless, conflicting results regarding the prognostic value of CD171 expression in renal cell carcinomas and gastrointestinal stromal tumors were published. In this study, CD171 expression was immunohistochemically analyzed in 5155 epithelial, mesenchymal, melanocytic, and lymphohematopoietic tumors to assess its utility in diagnostic pathology and to pinpoint potential targets for CD171-targeting therapy. A newly developed anti-CD171 rabbit monoclonal antibody, clone 014, was selected from the panel of commercially available CD171 antibodies. Immunohistochemistry was performed using Leica Bond Max automation and multitumor blocks containing up to 60 tumor samples. CD171 was constitutively and strongly expressed in neuroectodermal tumors such as schwannoma, neuroblastoma, and paraganglioma, whereas other mesenchymal tumors including schwannoma mimics showed only rarely CD171 positivity. Frequent CD171-expression was also detected in ovarian serous carcinoma, malignant mesothelioma, and testicular embryonal carcinoma. CD171 immunohistochemistry may have some role in immunophenotypic differential diagnosis of neurogenic tumors and pinpointing potential candidates for anti-CD171 therapy. Though, because of its rare expression and lack of predictive value, CD171 is neither a diagnostic nor prognostic marker for gastrointestinal stromal tumors. PMID:27419370

  18. Robotic Versus Laparoscopic Gastric Resection for Primary Gastrointestinal Stromal Tumors >5 cm: A Size-Matched and Location-Matched Comparison.

    PubMed

    de'Angelis, Nicola; Genova, Pietro; Amiot, Aurelien; Charpy, Cecile; Disabato, Mara; Belgaumkar, Ajay P; Chahrour, Ali; Legou, Francois; Azoulay, Daniel; Brunetti, Francesco

    2017-02-01

    This study compared robotic (RR) and laparoscopic resection (LR) for primary gastrointestinal stromal tumors (GISTs) of the stomach >5 cm. Twelve consecutive patients who underwent RR from 2012 to 2015 were matched for tumor size and location with 24 patients who underwent LR from 2000 to 2012. The median tumor size was 7.1 cm (range, 5.5 to 11.5). GISTs were resected by wedge resection (91.7%) or distal gastrectomy. The median RR operative time was longer than that of LR (162.5 vs. 130 min, respectively; P=0.004). Only 1 LR patient required conversion. The time to flatus and hospital stay were similar between groups. Overall, 3 patients developed minor postoperative complications that were medically treated. Mortality was nil. All resections were R0. No difference was observed in the incidence of recurrence. RR was significantly more expensive (+21.6%) than LR. RR appears to be safe and feasible for GISTs>5 cm, but is associated with longer operative times and greater costs.

  19. Stages of Gastrointestinal Carcinoid Tumors

    MedlinePlus

    ... carcinoid tumor is cancer that forms in the lining of the gastrointestinal tract. The gastrointestinal (GI) tract ... Rectum . Enlarge Gastrointestinal carcinoid tumors form in the lining of the gastrointestinal tract, most often in the ...

  20. A Role for Adjuvant RFA in Managing Hepatic Metastases from Gastrointestinal Stromal Tumors (GIST) After Treatment with Targeted Systemic Therapy Using Kinase Inhibitors

    SciTech Connect

    Hakimé, Antoine Cesne, Axel Le Deschamps, Frederic Farouil, Geoffroy Boudabous, Sana Aupérin, Anne Domont, Julien Debaere, Thierry

    2013-04-16

    PurposeThis study was designed to assess the role of radiofrequency ablation (RFA) in the multimodality management of gastrointestinal stromal tumors (GIST) in patients undergoing targeted tyrosine kinase inhibitor therapy (TKI) for liver metastases.MethodsOutcomes of 17 patients who underwent liver RFA for 27 metastatic GIST after TKI therapy, from January 2004 to March 2012, were retrospectively analyzed. Mean maximum tumor diameter was 2.5 ± 1 cm (range 0.9–4.5 cm). In seven patients (group A), RFA of all residual tumors was performed, with curative intent, and TKI therapy was discontinued. In five patients (group B), RFA of all residual tumors was performed upon achieving the best morphological response with TKI therapy, which was maintained after RFA. In another five patients (group C), RFA was performed on individual liver metastases which were progressive under TKI therapy.ResultsAll 27 targeted tumors were completely ablated, without local recurrence during the mean follow-up period of 49 months. No major complications occurred. Two minor complications were reported (11 %). Only two patients (both in group C) died at 20 and 48 months. Two-year progression-free survival (PFS) after RFA was 29 % in group A, 75 % in group B, and 20 % in group C.ConclusionsRFA in patients, previously treated with TKI, is feasible and safe. Our data suggest that RFA is a useful therapeutic option in patients with metastatic GIST and should be performed at the time of best clinical response with patient maintained under TKI after the procedure.

  1. SDHA loss-of-function mutations in KIT-PDGFRA wild-type gastrointestinal stromal tumors identified by massively parallel sequencing.

    PubMed

    Pantaleo, Maria A; Astolfi, Annalisa; Indio, Valentina; Moore, Richard; Thiessen, Nina; Heinrich, Michael C; Gnocchi, Chiara; Santini, Donatella; Catena, Fausto; Formica, Serena; Martelli, Pier Luigi; Casadio, Rita; Pession, Andrea; Biasco, Guido

    2011-06-22

    Approximately 10%-15% of gastrointestinal stromal tumors (GISTs) in adults do not harbor any mutation in the KIT or PDGFRA genes (ie, KIT/PDGFRA wild-type GISTs). Recently, mutations in SDHB and SDHC (which encode succinate dehydrogenase subunits B and C, respectively) but not in SDHA and SDHD (which encode subunits A and D, respectively) were identified in KIT/PDGFRA wild-type GISTs. To search for novel pathogenic mutations, we sequenced the tumor transcriptome of two young adult patients who developed sporadic KIT/PDGFRA wild-type GISTs by using a massively parallel sequencing approach. The only variants identified as disease related by computational analysis were in SDHA. One patient carried the homozygous nonsense mutation p.Ser384X, the other patient was a compound heterozygote harboring a p.Arg31X nonsense mutation and a p.Arg589Trp missense mutation. The heterozygous nonsense mutations in both patients were present in germline DNA isolated from peripheral blood. Protein structure analysis indicates that all three mutations lead to functional inactivation of the protein. This is the first report, to our knowle dge, that identifies SDHA inactivation as a common oncogenic event in GISTs that lack a mutation in KIT and PDGFRA.

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

    PubMed

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

    2016-03-23

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

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

    PubMed Central

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

    2016-01-01

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

  4. Imatinib-induced hyperbilirubinemia with UGT1A1 (*28) promoter polymorphism: first case series in patients with gastrointestinal stromal tumor

    PubMed Central

    Saif, Muhammad Wasif; Smith, Melissa Hennessey; Maloney, Antonia; Diasio, Robert B.

    2016-01-01

    Imatinib, an orally administered protein-tyrosine kinase inhibitor (TKI) is indicated for the treatment of chronic myeloid leukemia (CML) and gastrointestinal stromal tumor (GIST). Severe hepatotoxicity associated with imatinib is rare, and relationship to polymorphism of uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) expression and related frequency of hyperbilirubinemia or toxicity are not well known. We present a case series patients who developed hyperbilirubinemia while on oral administration imatinib for treatment of GIST. Genetic testing for polymorphism of UGT1A1 showed the first patient to be homozygous for the UGT1A1 TA7 (*28) polymorphism and the second patient heterozygous for the UGT1A1 TA1 (*28) polymorphism. The first patient had to stop imatinib due to severe and persistent hyperbilirubenemia peaking >3 despite reducing imatininb to only 100 mg every other day while the second patient improved at this dose. Our case series represent the first data associating UGT1A1 polymorphism and imatinib in patients being treated for GIST. Given the prevalence of Gilbert’s syndrome and the increasing use of imatinib, we encourage physicians to be aware of this possible toxicity as hepatotoxicity can be fatal if not managed in a timely fashion. This association is also timely due to recent FDA requirement for testing UGT1A1 polymorphism for nilotinib, another TKI. PMID:27708529

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

    SciTech Connect

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

    2014-08-15

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

  6. The Therapeutic Response of Gastrointestinal Stromal Tumors to Imatinib Treatment Assessed by Intravoxel Incoherent Motion Diffusion-Weighted Magnetic Resonance Imaging with Histopathological Correlation

    PubMed Central

    Zhang, Chunfang; Wang, He; Cheng, Jin; Wu, Weizhen; Hong, Nan; Wang, Yi

    2016-01-01

    Purpose To exploit the intravoxel incoherent motion (IVIM) diffusion-weighted (DW) MRI when evaluating the therapeutic response of gastrointestinal stromal tumors (GIST) to Imatinib in a mouse model. Materials and Methods Mice with xenografts bearing cells from the GIST-T1 cell line were randomly divided into a treated group receiving Imatinib and a control group. DWMRI scans with 14 b-values (0–1500 s/mm2) were performed before and after treatment (days 1, 3 and 7). IVIM related parameters perfusion fractions (fp) and perfusion-related diffusion coefficients (D*) and the conventional apparent diffusion coefficients (ADC) were calculated by fitting the DWMRI signal decay. The mean changes from baseline to each post-treatment time point for each measurement (ΔADC, Δfp and ΔD*) were calculated. The differences of mean changes between the two groups were tested for statistical significance. Histopathological analyses including Ki-67, CD31, TUNEL and H&E were conducted in conjunction with the MRI scans. Results Increases in ADC of the treated group were higher than those of the control group after treatment, whereas statistical significances were not observed. Compared to the control group, D* in the treated group decreased significantly (ΔD*treated = -41%, -49%, and -49% with P = 0.0001, 0.0001 and 0.0001), and fp increased significantly (Δfptreated = 79%, 82% and 110%, with P = 0.001, 0.0001 and P = 0.0007) on days 1, 3 and 7 after treatment. Histopathological analyses demonstrated different tumor tissue characteristics between the treated and control groups. Conclusion IVIM measurements may serve as more sensitive imaging biomarkers than ADC when assessing GIST response to Imatinib as early as one day after treatment. PMID:27911930

  7. Gastrointestinal stromal tumors with KIT exon 9 mutations: Update on genotype-phenotype correlation and validation of a high-resolution melting assay for mutational testing.

    PubMed

    Künstlinger, Helen; Huss, Sebastian; Merkelbach-Bruse, Sabine; Binot, Elke; Kleine, Michaela Angelika; Loeser, Heike; Mittler, Jens; Hartmann, Wolfgang; Hohenberger, Peter; Reichardt, Peter; Büttner, Reinhard; Wardelmann, Eva; Schildhaus, Hans-Ulrich

    2013-11-01

    KIT exon 9 mutations in gastrointestinal stromal tumors (GISTs) are highly relevant and have direct therapeutic implications. In this context, we established and validated a fast and sensitive high-resolution melting assay. Analyzing 126 primary and 18 metastatic KIT exon 9-mutated cases from our registry, we demonstrate that the mutational spectrum of exon 9 is broader than previously thought and describe 3 novel mutations. Including these cases and the common p.A502_Y503dup mutation, we provide a comprehensive list of all known KIT exon 9 mutations according to the Human Genome Variation Society nomenclature. Two of the newly described mutations were associated with an aggressive phenotype and tumor progression while being treated with 400 mg imatinib, indicating that also GIST with rare exon 9 mutations could be treated with increased imatinib dosage. On the basis of >1500 GISTs from our registry, we have determined the frequency of KIT exon 9 mutations to be 9.2% among all GISTs and 22.5% among small-bowel cases. We describe for the first time that nearly 20% of exon 9-mutated GIST occur in the stomach or rectum. Furthermore, we provide first evidence that exon 9-mutated GISTs metastasize significantly more often to the peritoneum than to the liver. Performing extensive statistical analyses on data from our registry and from the literature, we demonstrate that KIT exon 9 mutations are neither associated with intermediate-risk/high-risk status nor overrepresented among metastatic lesions. Thus, we conclude that exon 9 mutations per se do not have prognostic relevance.

  8. [Extragastrointestinal stromal tumor (EGIST)--a case review].

    PubMed

    Kolarík, J; Drápela, J

    2012-04-01

    Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract. Due to the presence of thyrosine kinase receptors within the tumor tissue, GIST is thought to originate from gastrointestinal pacemaker cells, the intersticial cells of Cajal. Tumors with the same morphological and imunohistochemical characteristics detected outside the gastrointestinal tract, are called extragastrointestinal stromal tumors (EGIST). Biological characteristics of these tumors is uncertain and the malignancy rates are difficult to predict. Surgical R0 resection in resecable tumors is the only option with the potential for complete cure. Nevertheless, the recurrence rates are high. Adjuvant biological treatment with imatinib, a thyrosine kinase inhibitor, reduces the risk of relapses. Imatinib administration is also the principal treatment method in metastatic GIST disorders. The article offers a short and complex overview of gastrointestinal stromal tumor (GIST) problematics and presents a case report of a patient suffering from EGIST of mesocolon transversum treated by R0 resection which was performed under multidisciplinary cooperation, with a specialist follow up.

  9. Laparoscopic resection of duodenal gastrointestinal stromal tumour

    PubMed Central

    Zioni, Tammy; Dizengof, Vitaliy; Kirshtein, Boris

    2017-01-01

    Only a few studies have revealed using laparoscopic technique with limited resection of gastrointestinal stromal tumour (GIST) of the duodenum. A 68-year-old man was admitted to the hospital due to upper gastrointestinal (GI) bleeding. Evaluation revealed an ulcerated, bleeding GI tumour in the second part of the duodenum. After control of bleeding during gastroduodenoscopy, he underwent a laparoscopic wedge resection of the area. During 1.5 years of follow-up, the patient is disease free, eats drinks well, and has regained weight. Surgical resection of duodenal GIST with free margins is the main treatment of this tumour. Various surgical treatment options have been reported. Laparoscopic resection of duodenal GIST is an advanced and challenging procedure requiring experience and good surgical technique. The laparoscopic limited resection of duodenal GIST is feasible and safe, reducing postoperative morbidity without compromising oncologic results. PMID:28281485

  10. Short- and Long-Term Outcomes of Laparoscopic Versus Open Resection for Gastric Gastrointestinal Stromal Tumors: A Propensity Score-Matching Analysis.

    PubMed

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

    2016-04-01

    Published reports on laparoscopic resection of gastric gastrointestinal stromal tumor (GIST) were limited to small experiences and selection bias. Two hundred fourteen patients who underwent primary gastric GIST resection at our institution (January 2006-December 2012) were identified from a prospectively collected database. Laparoscopic resections (LAP) were performed in 133 patients, and open resections (OPEN) were performed in 81 patients. The short- and long-term outcomes were analyzed using propensity-score matching (PSM) by comparing the clinicopathological factors between these groups. The tumor resection method and tumor size were significantly different between the LAP and OPEN groups. After PSM, there were no differences (P > 0.05) in these clinicopathological factors. The LAP group had less blood loss and shorter operation time, time to first flatus, time to first fluid diet, time to gastric tube removal, and postoperative stay before PSM. In addition, there were no differences regarding the time of drainage tube removal or hospitalization expense. Other than the time of gastric tube removal, which was similar in these 2 groups, the short-term outcomes were similar before and after PSM. The rates of postoperative complications in the LAP and OPEN groups were 6.8% and 22.8%, respectively, before PSM (P = 0.001) and 5.6% and 22.5%, respectively, after PSM (P = 0.004). The multivariate analyses for complications showed that tumors were located in the middle of the stomach, and the operation method and proximal gastrectomy were independent risk factors before and after PSM. The 5-year cumulative survival rates in the LAP and OPEN groups were 95.4% and 85.9%, respectively, (P = 0.07) before PSM and 93.1% and 91.9%, respectively, (P = 0.69) after PSM (not significantly different). Laparoscopic resection for gastric GISTs had better short-term outcomes and similar long-term outcomes compared with open surgery. Localized gastric GISTs can be

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

    PubMed Central

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

    2015-01-01

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

  12. Surgical Management of Wild-Type Gastrointestinal Stromal Tumors: A Report From the National Institutes of Health Pediatric and Wildtype GIST Clinic.

    PubMed

    Weldon, Christopher B; Madenci, Arin L; Boikos, Sosipatros A; Janeway, Katherine A; George, Suzanne; von Mehren, Margaret; Pappo, Alberto S; Schiffman, Joshua D; Wright, Jennifer; Trent, Jonathan C; Pacak, Karel; Stratakis, Constantine A; Helman, Lee J; La Quaglia, Michael P

    2016-12-28

    Purpose Wild-type gastrointestinal stromal tumors (WT-GISTs) that lack KIT or PDGFRA mutations represent a unique subtype of GIST that predominantly affects children. We sought to determine the effect on event-free survival (EFS) of staging variables, extent of resection, and repeat resection of tumors. Methods In 2008, a WT-GIST clinic was established at the National Cancer Institute, allowing the development of a large clinical database. We included participants who underwent resection of WT-GIST. Associations with EFS (ie, freedom from disease progression or recurrence) were evaluated using the Kaplan-Meier method and Cox proportional hazards modeling. Results Among 76 participants with WT-GISTs, the median follow-up was 4.1 years. Overall EFS (± SE) was 72.6 ± 5.4% at 1 year, 57.6 ± 6.2% at 2 years, 23.7 ± 6.0% at 5 years, and 16.3 ± 5.5% at 10 years postoperatively. Hazard of disease progression or recurrence was significantly increased for patients with metastatic disease (adjusted hazard ratio [AHR], 2.3; 95% CI, 1.0 to 5.1; P = .04) and > 5 mitoses per 50 high-power fields (AHR, 2.5; 95% CI, 1.1 to 6.0; P = .03), whereas there was no significant effect of negative microscopic resection margins (AHR, 0.9; 95% CI, 0.4 to 2.2; P = 0.86). There was no association between type of gastric resection (ie, anatomic v partial/wedge) and EFS ( P = .67). Repeated resection after the initial resection was significantly associated with decreasing postoperative EFS ( P < .01). Five patients (6%) died after initial enrollment in 2008. Conclusion WT-GIST is an indolent disease, and most patients survive with disease progression. We found no improvement in EFS with more extensive or serial resections. Disease progression or recurrence may be more closely related to tumor biology than surgical management. These data suggest that resections for WT-GISTs be restricted to the initial procedure and that subsequent resections be performed only to address symptoms such as

  13. Imatinib treatment for gastrointestinal stromal tumour (GIST).

    PubMed

    Lopes, Lisandro F; Bacchi, Carlos E

    2010-01-01

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

  14. Imatinib treatment for gastrointestinal stromal tumour (GIST)

    PubMed Central

    Lopes, Lisandro F; Bacchi, Carlos E

    2010-01-01

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

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

    PubMed

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

    2015-01-01

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

  16. Targeted therapy of gastrointestinal stromal tumours

    PubMed Central

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

    2016-01-01

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

  17. What Are Gastrointestinal Stromal Tumors?

    MedlinePlus

    ... the GI tract, called the interstitial cells of Cajal (ICCs). ICCs are cells of the autonomic nervous system, the part of the nervous system that regulates body processes such as digesting food. ICCs are sometimes ...

  18. Treatment Option Overview (Gastrointestinal Carcinoid Tumors)

    MedlinePlus

    ... carcinoid tumor is cancer that forms in the lining of the gastrointestinal tract. The gastrointestinal (GI) tract ... Rectum . Enlarge Gastrointestinal carcinoid tumors form in the lining of the gastrointestinal tract, most often in the ...

  19. Treatment Options for Gastrointestinal Carcinoid Tumors

    MedlinePlus

    ... carcinoid tumor is cancer that forms in the lining of the gastrointestinal tract. The gastrointestinal (GI) tract ... Rectum . Enlarge Gastrointestinal carcinoid tumors form in the lining of the gastrointestinal tract, most often in the ...

  20. General Information about Gastrointestinal Carcinoid Tumors

    MedlinePlus

    ... carcinoid tumor is cancer that forms in the lining of the gastrointestinal tract. The gastrointestinal (GI) tract ... Rectum . Enlarge Gastrointestinal carcinoid tumors form in the lining of the gastrointestinal tract, most often in the ...

  1. [Subepithelial tumors of the gastrointestinal tract].

    PubMed

    Stupnik, Silvio; Rafaelli, Claudio; González, Graciela Osorio; Pestalardo, María Luján; Quesada, Matías; Viúdez, Pedro

    2009-06-01

    The subepithelial lesions of the gastrointestinal tract are related to mesenchymal tumors and 80% of them are GIST (gastrointestinal stromal tumors). However, there are also other tumors, such as: leiomyomas, schwannomas, lipomas, glomus tumors, carcinoid tumors, aberrant pancreas and polyps or inflammatory tumors. Diagnosis of submucosal tumors is often performed during routine endoscopic examination, they are frequently located at the stomach and in most cases are clinically evidenced by their complications. Endoscopic ultrasonography (EUS) is the elected method for their staging; but other imaging diagnosis methods include computed tomography (CT), magnetic resonance imaging (MRI) and positron emission tomography scan (PET). The differential diagnosis is made by inmunohistochemical techniques, revealing in the GIST the expression of the antigen CD117, and prognostic factors are determined by size and mitotic index. Surgery is the recommended therapeutic, although in small lesions not exceeding 2 cm it has also been suggested the endoscopic resection guided by EUS and a watchful behaviour based on periodical controls in lesions with benignity criteria. The series here exhibited (2 GIST 1 lyposarcoma, 1 schwannoma and 1 inflammatory fibroid polyp) shows that all these tumors were symptomatic; have been diagnosed using endoscopy and recognized by means of histopathology and immunohistochemical analysis after surgery.

  2. Targeted ultra-deep sequencing unveils a lack of driver-gene mutations linking non-hereditary gastrointestinal stromal tumors and highly prevalent second primary malignancies: random or nonrandom, that is the question

    PubMed Central

    Kuo, Yung-Chia; Hsu, Hung-Chih; Chen, Jen-Shi; Chen, Tse-Ching; Wu, Ren-Chin; Chiu, Cheng-Tang; Yeh, Chun-Nan; Yeh, Ta-Sen

    2016-01-01

    The association of non-hereditary (sporadic) gastrointestinal stromal tumors (GISTs) and second primary malignancies is known to be nonrandom, although the underlying molecular mechanisms remain unknown. In this study, 136 of 749 (18.1%) patients with sporadic GISTs were found to have additional associated cancers, with gastrointestinal and genitourinary/gynecologic/breast cancers being the most prevalent. Gene mutations in GISTs and their associated colorectal cancers (CRCs) (n=9) were analyzed using a panel of 409 cancer-related genes, while a separate group of 40 sporadic CRCs not associated with GISTs served as controls. All 9 of the GISTs had either KIT (8 of 9) or PDGFRA (1 of 9) mutations that were not present in their associated CRCs. Conversely, all but one of the 9 GIST-associated CRCs exhibited an APC mutation, a TP53 mutation or both, while none of their corresponding GISTs harbored either APC or TP53 mutations. The genetic profile of CRCs with and without associated GISTs did not differ. Although population-based studies and case series worldwide, including ours, have unanimously indicated that the GIST-CRC association is nonrandom, our targeted ultra-deep sequencing unveiled a lack of driver-gene mutations linking sporadic GISTs to highly prevalent second primaries. Further studies are needed to elucidate other genetic alterations that may be responsible for this puzzling contradiction. PMID:27806309

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

    MedlinePlus

    ... About Gastrointestinal Carcinoid Tumors What Are the Key Statistics About Gastrointestinal Carcinoid Tumors? Although the exact number ... a Gastrointestinal Carcinoid Tumor? What Are the Key Statistics About Gastrointestinal Carcinoid Tumors? What’s New in Gastrointestinal ...

  4. BRAF exon 15 mutations in pediatric renal stromal tumors: prevalence in metanephric stromal tumors.

    PubMed

    Marsden, Lily; Jennings, Lawrence J; Gadd, Samantha; Yu, Min; Perlman, Elizabeth J; Cajaiba, Mariana M

    2017-02-01

    Metanephric stromal tumors (MSTs) are rare renal stromal tumors that predominantly affect children. They belong to the metanephric family of tumors, along with metanephric adenofibroma and metanephric adenoma. The previous documentation of BRAF exon 15 mutations in 88% of metanephric adenomas and in isolated cases of metanephric adenofibroma prompted us to investigate the prevalence of these mutations in MSTs and in other pediatric renal stromal tumors. In this study, 17 MSTs, 22 congenital mesoblastic nephromas, and 6 ossifying renal tumors of infancy were selected for BRAF exon 15 testing. Tumor genomic DNA was extracted from formalin-fixed paraffin-embedded tissue, followed by polymerase chain reaction amplification and Sanger dideoxy sequencing with primers flanking the BRAF exon 15 gene. BRAF exon 15 mutations were found in 11 (65%) of the 17 cases of MST, all corresponding to a thymidine-to-adenine substitution at codon 600 (BRAF V600E). All other renal stromal tumors tested were negative for BRAF exon 15 mutations. In conclusion, BRAF V600E mutations are encountered in most MSTs, supporting a link with other metanephric tumors and suggesting a clonal event possibly affecting primordial renal cells. In addition, BRAF V600E mutations have been associated with oncogene-induced senescence in other benign tumors, providing clues to the pathogenesis of metanephric neoplasms in keeping with their overall benign behavior. Our results also suggest a potential diagnostic use for BRAF exon 15 mutations in differentiating MSTs from other pediatric renal stromal tumors, particularly in limited samples.

  5. Gastrointestinal stromal tumors - quantitative detection of the Ki-67, TPX2, TOP2A, and hTERT telomerase subunit mRNA levels to determine proliferation activity and a potential for aggressive biological behavior.

    PubMed

    Kalfusova, A; Hilska, I; Krskova, L; Kalinova, M; Linke, Z; Kodet, R

    2016-01-01

    Gastrointestinal stromal tumors (GISTs) have an unpredictable biological potential ranging from benign to malignant. Molecular markers involved in the mechanisms of proliferation and cellular senescence may provide additional information about biological behavior of the tumor. The aim of the present study was to investigate Ki-67, TPX2, TOP2A and hTERT mRNA expression levels in specimens from patients with GISTs to define relationships between proliferation activity and biological potential and progression of the disease. We measured Ki-67, TPX2, TOP2A and hTERT mRNA levels using quantitative real-time reverse transcription PCR (RQ RT PCR). The highest Ki-67, TPX2, TOP2A and hTERT mRNA expression levels were found in the highly proliferative BLs (18 specimens), in comparison with GISTs (137 specimens) and LMSs (9 specimens). Patients with GISTs and adequate information about mitotic activity, tumor size and anatomical site (84 specimens) were divided into two groups - GISTs with benign (29 patients) and with malignant (55 patients) potential. We observed association between higher Ki-67, TPX2 and hTERT mRNA levels and the GISTs with malignant potential. Univariate analysis (57 patients with available follow-up information) of survival (Kaplan Meier curves method) revealed a correlation between higher levels of TPX2, Ki-67 and hTERT markers and shorter event-free survival (EFS) or poorer overall survival (OS). The results demonstrate the importance of quantitative assessment of the proliferation activity in GISTs. Proliferation markers of Ki-67, TPX2, TOP2A and hTERT are suitable markers for detection the proliferation activity and telomerase activity of these tumors. Furthermore, the assessment of TPX2, Ki-67 and hTERT expression levels is appropriate for determination of malignant potential of GISTs.

  6. Giant rectal gastrointestinal stromal tumours: a diagnostic and therapeutic challenge

    PubMed Central

    Alder, L.S.; Elver, G.; Foo, F.J.; Dobson, M.

    2013-01-01

    Gastrointestinal stromal tumour (GIST are the most common mesenchymal tumours; however, rectal GISTs account for <5%. In the pelvis they represent a diagnostic challenge with giant GISTs likely to be malignant. They may present with urological, gynaecological or rectal symptoms. Sphincter-preserving surgery can be aided by neoadjuvant therapy. We present an uncommon case of giant rectal GIST masquerading as acute urinary retention. PMID:24968434

  7. Microfluidic deletion/insertion analysis for rapid screening of KIT and PDGFRA mutations in CD117-positive gastrointestinal stromal tumors: diagnostic applications and report of a new KIT mutation.

    PubMed

    Zamò, Alberto; Bertolaso, Anna; Franceschetti, Ilaria; Weirich, Gregor; Capelli, Paola; Pecori, Sara; Chilosi, Marco; Hoefler, Heinz; Menestrina, Fabio; Scarpa, Aldo

    2007-04-01

    Gastrointestinal stromal tumors (GISTs) frequently harbor mutations in the KIT and PDGFRA genes, the presence and type of which correlate with the response to the kinase inhibitor imatinib mesylate. Because most GIST mutations are deletions/insertions, we used a microfluidic apparatus to detect these size variations in polymerase chain reaction-amplified DNA. This approach, termed microfluidic deletion/insertion analysis (MIDIA), identified mutations in 30 of 50 DNA samples from paraffin-embedded CD117-positive GISTs (60%), comprising 25 deletions and five insertions. Sequencing of 14 MIDIA-positive samples confirmed the deletions/insertions, including two 3-bp alterations. Sequencing of all 20 MIDIA-negative samples also showed highly consistent results with MIDIA because 10 cases were wild type and eight displayed a single base substitution in which detection by MIDIA was not expected. Sequencing also revealed a 3-bp deletion undetected by MIDIA, thus establishing the resolution limit of MIDIA at deletions/insertions >or=3 bp. Denaturing high-pressure liquid chromatography analysis confirmed all mutations detected by MIDIA and sequencing. We pro-pose MIDIA as the first step in mutational screening of GIST because it allowed the detection of 75% of mutated cases (94% of deletions/insertions) in less than 30 minutes after polymerase chain reaction amplification and at a lower cost compared with denaturing high-pressure liquid chromatography and sequencing, which might then be used only for MIDIA-negative cases.

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

    PubMed Central

    2011-01-01

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

  9. Insulin-like Growth Factor (IGF) system and gastrointestinal stromal tumours (GIST): present and future.

    PubMed

    Nannini, Margherita; Biasco, Guido; Astolfi, Annalisa; Urbini, Milena; Pantaleo, Maria A

    2014-02-01

    In the last decades, the concept that Insulin-like Growth Factor (IGF) axis plays a key role in several steps of tumorigenesis, cancer growth and metastasis has been widely documented. The aberration of the IGF system has been described in many kinds of tumours, providing several lines of evidence in support of IGF receptor type 1 (IGF1R) as molecular target in cancer treatment. Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumor of the gastrointestinal tract, commonly characterized in most cases by KIT and PDGFRA gain mutations. Beyond to the well recognized KIT and PDGFRA gain mutations, in the last years other molecular aberrations have been investigated. Recently, several lines of evidence about the involvement of the IGF system in GIST have been accumulated. The aim of this review is to report all current data about the IGF system involvement in GIST, focusing on the current clinical implication and future perspectives.

  10. Mesenteric gastrointestinal stromal tumour presenting as intracranial space occupying lesion

    PubMed Central

    Puri, Tarun; Gunabushanam, Gowthaman; Malik, Monica; Goyal, Shikha; Das, Anup K; Julka, Pramod K; Rath, Goura K

    2006-01-01

    Background Gastrointestinal stromal tumours (GIST) usually present with non-specific gastrointestinal symptoms such as abdominal mass, pain, anorexia and bowel obstruction. Methods We report a case of a 42 year old male who presented with a solitary intracranial space occupying lesion which was established as a metastasis from a mesenteric tumour. Results The patient was initially treated as a metastatic sarcoma, but a lack of response to chemotherapy prompted testing for CD117 which returned positive. A diagnosis of mesenteric GIST presenting as solitary brain metastasis was made, and the patient was treated with imatinib. Conclusion We recommend that all sarcomas with either an intraabdominal or unknown origin be routinely tested for CD117 to rule out GIST. PMID:17105654

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

    PubMed Central

    Głuszek, Stanisław; Kozieł, Dorota

    2014-01-01

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

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

    PubMed

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

    2015-12-08

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

  13. [A rare case of bone metastasis from gastro-intestinal stromal tumour: place of radiotherapy].

    PubMed

    Heymann, S; Imperiale, A; Schlund-Schoettel, E; Sauer, B; Dourthe, L-M

    2014-01-01

    Gastro-intestinal stromal tumours are the most common mesenchymal neoplasms of the gastrointestinal tract. Their usual metastatic sites are the liver and the peritoneum, but gastro-intestinal stromal tumours rarely metastasize to the bones. We report the case of a 56-year-old male presenting with bone lesions six years after initial surgical resection. We discuss through this paper the possibilities of management of these lesions and the place of radiotherapy.

  14. Sclerosing stromal tumor of the ovary in a premenarchal female.

    PubMed

    Fefferman, Nancy R; Pinkney, Lynne P; Rivera, Rafael; Popiolek, Dorota; Hummel-Levine, Pascale; Cosme, Jaqueline

    2003-01-01

    Sclerosing stromal tumor (SST) is a rare benign ovarian neoplasm of stromal origin with less than 100 cases reported in the literature. Unlike the other stromal tumors, thecomas and fibromas, which tend to occur in the fifth and sixth decades, sclerosing stromal tumors predominantly affect females in the second and third decades. Computed tomography (CT), magnetic resonance imaging (MRI), and ultrasound findings have been described, but have not been reported previously in the pediatric literature. We present a case of SST of the ovary in a 10-year-old premenarchal female, the youngest patient to our knowledge reported in the literature, and describe the ultrasound and CT findings with pathologic correlation.

  15. Paraneoplastic Hypoglycaemia: A Rare Manifestation of Pelvic Gastrointestinal Stromal Tumour

    PubMed Central

    Hadi, Rahat; Mehrotra, Kiranpreet; Rastogi, Shivani; Masood, Shakeel

    2017-01-01

    Non-Islet Cell Tumour Induced Hypoglycaemia (NICTH), presenting with recurrent fasting hypoglycaemia is a very rare paraneoplastic syndrome. It usually presents with large metastatic mesenchymal tumours. NICTH secondary to Gastrointestinal Stromal Tumour (GIST) is even rarer. Diagnosis of NICTH is based on the low serum insulin level, low serum concentrations of Insulin Like Growth Factor (IGF-I) and IGF binding protein- III (IGFBP-III) in combination with elevated concentrations of pro-IGF-II. Various Immunohistochemical (IHC) markers are integral to diagnosis of GIST namely 2-deoxyglucose-6-phosphate phosphatase -1(DOG-1), Cluster Differentiation 34 (CD 34), Cluster Differentiation 117 (CD117). The management requires prompt intravenous hydration and glucose infusions followed by surgical resection. We hereby, report a rare case of a 65-year-old female with intractable fasting hypoglycaemia due to overproduction of "big" insulin-like growth factor II diagnosed to have pelvic GIST and managed by Steroids and Imatinib.

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

    PubMed

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

    2009-01-01

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

  17. Bilateral Sclerosing Stromal Ovarian Tumor in an Adolescent

    PubMed Central

    Naidu, Anjani; Chung, Betty; Simon, Mitchell; Marshall, Ian

    2015-01-01

    Sclerosing stromal tumor of the ovary is a rare, benign, sex cord stromal tumor occurring predominantly in younger women in the 2nd and 3rd decades of life. It typically presents unilaterally with only 2 previously reported cases of bilateral presentation. Common clinical presentations include pelvic or abdominal pain, a mass, or menstrual changes. Although occasionally presenting with hormonal manifestations, virilization as a result of androgen production by the tumor is rare. Here we present an extremely rare case of a sclerosing stromal ovarian tumor in a 14-year-old patient with bilateral presentation and with clinical and biochemical evidence of hyperandrogenemia. PMID:26064755

  18. Genetics Home Reference: gastrointestinal stromal tumor

    MedlinePlus

    ... membrane of certain cell types and stimulate signaling pathways inside the cell. Receptor proteins have specific sites ... of a series of proteins in multiple signaling pathways. These signaling pathways control many important cellular processes, ...

  19. How Are Gastrointestinal Stromal Tumors Diagnosed?

    MedlinePlus

    ... is injected into the blood. The amount of radioactivity used is very low. Because cancer cells in ... special camera creates a picture of areas of radioactivity in your body. PET scan images are not ...

  20. How Are Gastrointestinal Stromal Tumors Staged?

    MedlinePlus

    ... The cancer has spread to nearby lymph nodes. M categories for GIST M0: The cancer has not ... lungs). Stage grouping Once the T, N, and M categories have been determined, this information is combined, ...

  1. What Happens after Treatment for Gastrointestinal Carcinoid Tumors?

    MedlinePlus

    ... for Gastrointestinal Carcinoid Tumors? For some people with gastrointestinal (GI) carcinoid tumor, treatment may remove or destroy the cancer. Completing treatment can be both stressful and exciting. ...

  2. Necrotizing cellulitis of the abdominal wall, caused by Pediococcus sp., due to rupture of a retroperitoneal stromal cell tumor

    PubMed Central

    Michalopoulos, Nick; Arampatzi, Stergiani; Papavramidis, Theodossis S.; Kotidis, Efstathios; Laskou, Styliani; Papavramidis, Spiros T.

    2013-01-01

    INTRODUCTION Soft tissue necrotizing infections are a significant cause of morbidity and mortality. The aim of this study is to present a patient with necrotizing infection of abdominal wall resulting from the rupture of a retroperitoneal stromal tumor. PRESENTATION OF CASE We present a 60-year-old Caucasian male patient with necrotizing infection of abdominal wall secondary to the rupture of a retroperitoneal stromal tumor. The patient was initially treated with debridement and fasciotomy of the anterior abdominal wall. Laparotomy revealed purulent peritonitis caused by infiltration and rupture of the splenic flexure by the tumor. Despite prompt intervention the patient died 19 days later. The isolated microorganism causing the infection was the rarely identified as cause of infections in humans Pediococcus sp., a gram-positive, catalase-negative coccus. DISCUSSION Necrotizing infections of abdominal wall are usually secondary either to perineal or to intra-abdominal infections. Gastrointestinal stromal cell tumors could be rarely complicated with perforation and abscess formation. In our case, the infiltrated by the extra-gastrointestinal stromal cell tumor ruptured colon was the source of the infection. The pediococci are rarely isolated as the cause of severe septicemia. CONCLUSION Ruptured retroperitoneal stromal cell tumors are extremely rare cause of necrotizing fasciitis, and before this case, Pediococcus sp. has never been isolated as the responsible agent. PMID:23357010

  3. Large gastrointestinal stromal tumours of the stomach: Is laparoscopy reasonable?

    PubMed Central

    Severino, Beatrice Ulloa; Fuks, David; Lainas, Panagiotis; Blain, Antoine; Validire, Pierre; Ferraz, Jean-Marc; Perniceni, Thierry; Gayet, Brice

    2016-01-01

    BACKGROUND: Laparoscopic resection (LR) offers significant advantages compared to open resections for gastric gastrointestinal stromal tumours (GISTs). We aimed to evaluate whether LR outcomes jeopardised short and long-term outcomes of patients with large GISTs. PATIENTS AND METHODS: Among 50 patients undergoing surgery for gastric GISTs, 12 underwent LR for large GISTs (>5 cm). Their characteristics, perioperative results and survival were retrospectively compared to those of 22 patients who underwent LR for ‘small GIST’. RESULTS: The two groups were similar regarding demographics, rate of wedge resection and mean blood loss. No patient required transfusion or conversion. Operative time was significantly increased in the ‘large GIST’ group (160 min vs 112 min, P = 0.001). Mean tumour size was significantly lower in the ‘small GIST’ group (8.4 cm vs 2.4 cm, P = 0.0001). Resection margins were negative. The mortality rate was nil and the overall morbidity rates was similar in both groups. Median length of hospital stay was significantly increased in the ‘large GIST’ group (7 days vs 5 days, P = 0.004). Median follow-up was 47 months and one patient in the ‘small GIST’ group developed recurrence and died during follow-up 11 years after surgery. No patient died during follow-up. CONCLUSIONS: LR for large GISTs is safe and technically feasible and does not negatively influence the oncologic course. Prospective randomised trials should be performed before using this approach in routine surgical care. PMID:27073308

  4. Altered expression profile of micrornas in gastric stromal tumor.

    PubMed

    Xiao, Jun; Wang, Qi-xian; Zhu, You-qing

    2015-12-01

    MicroRNAs (miRNAs) play important roles in carcinogenesis, but the global miRNA expression profile in gastric stromal tumor tissues remains unclear. This study was to examine the miRNA expression profile in gastric stromal tumor tissues and explore the function of dysregulated miRNAs by performing gene ontology (GO) and pathway enrichment analysis. Total RNA was extracted and purified from 3 pairs of frozen gastric stromal tumor tissues and the adjacent non-tumor tissues by using mirVana™ miRNA isolation kit. The miRNA expression was analyzed with Affymetrix microarrays (version 4.0) containing 2578 human mature microRNA probes. The dysregulated microRNAs were validated by quantitative RT-PCR in 30 pairs of gastric stromal tumor tissues. The target gene of the dysregulated microRNAs was predicted by miRanda, TargetScan and PicTar. GO and pathway enrichment analysis was conducted to examine the potential function of miR-3178 and miR-193a-5p. The results showed that there were 12 differently expressed microRNAs in gastric stromal tumor tissues, among which 10 miRNAs were down-regulated, and 2 were up-regulated (P<0.05). The validation results by RT-PCR were in accordance with those by microRNA microarry. GO analysis found that the target genes of miR-3178 were involved in 5 GO terms and those of miR-193a-5p in 7 GO terms in level 2. Pathway enrichment analysis suggested that miR-3178 and miR-193a-5p were related to 57 and 122 signaling pathways, respectively. It was concluded that gastric stromal tumor displays a unique miRNA signature. This specific expression may become a new diagnostic and prognostic biomarker for gastric stromal tumor. miR-3178 and miR-193a-5p function as suppressive microRNAs, and they may also become diagnosis and treatment targets for gastric stromal tumor.

  5. Bevacizumab in Treating Patients With Recurrent Sex Cord-Stromal Tumors of the Ovary

    ClinicalTrials.gov

    2017-02-03

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

  6. A rare ovarian tumor, leydig stromal cell tumor, presenting with virilization: a case report

    PubMed Central

    Aminimoghaddam, Soheila; Hashemi, Forough

    2012-01-01

    Leydig stromal cell tumor is a rare ovarian tumor that belongs to the group of sex-cord stromal tumors. They produce testosterone leading to hyperandrogenism. We present a 41yr old woman with symptoms of virilization and a mass of right adenex via ultra Sonography, and a rise of total and free serum testosterone. An ovarian source of androgen was suspected and a surgery performed. A diagnosis of leydig-stromal cell tumor was confirmed. Our report is a reminder that although idiopathic hirsutism and other benign androgen excess disorder like Polycystic Ovarian Syndrome (PCOs) are common, ovarian mass should be considered in differential diagnosis. PMID:23482693

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed Central

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

    2016-01-01

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

  9. Do We Know What Causes Gastrointestinal Carcinoid Tumors?

    MedlinePlus

    ... We Know What Causes Gastrointestinal Carcinoid Tumors? Can Gastrointestinal Carcinoid Tumors Be Prevented? Back To Top Imagine a world free from cancer. Help make it a reality. DONATE Cancer Information ...

  10. Oncological emergencies associated with gastrointestinal tumors

    PubMed Central

    Prenen, Klaas; Prenen, Hans

    2015-01-01

    Oncological emergencies are defined as acute life-threatening conditions in cancer patients either as a result of the malignancy or as a result of its treatment. In this review, we focus on oncological emergencies associated with gastrointestinal tumors. They can be categorized by their system of origin as hematologic, neurologic or metabolic. Furthermore, we discuss mechanical emergencies such as intestinal obstruction and vena cava superior syndrome as well as acute gastrointestinal bleeding and pulmonary embolism. The patients’ performance status as well as prognosis are essential during decision making for optimal treatment. PMID:26424367

  11. Criteria for malignancy in gastrointestinal endocrine tumors.

    PubMed

    Bordi, Cesare; D'Adda, Tiziana; Azzoni, Cinzia; Pizzi, Silvia; Bottarelli, Lorena; Mormandi, Francesca; Antonetti, Tommaso; Luong, Tu Vinh; Rindi, Guido

    2006-01-01

    In contrast with the large amount of data generated from endocrine tumors of the pancreas, sparse and mostly unconfirmed data are available on the criteria for the assessment of malignancy risk and patient outcome in endocrine tumors of the gastrointestinal tract. In these conditions the 2000 WHO classification with its standardized scheme of pathologic report constitutes a framework facilitating the assessment of tumor malignancy and has been regarded as useful for clinical purposes, providing the basis for proper management of the patients and for the design of treatment protocols. The classification is based on a combination of pathological and clinical features with parameters specific for each organ in which the endocrine tumors originate. Three main categories, one further subdivided into two subgroups, are considered: (1) well-differentiated endocrine tumors, further subdivided into tumors with benign and with uncertain behavior; (2) well-differentiated endocrine carcinomas, low grade; and (3) poorly differentiated endocrine carcinomas, high grade. In this review the differential tumor characteristics between the different categories are summarized. Moreover, the relevance of additional features with respect to tumor prognostication, chiefly the Ki-67 proliferation index and malignancy-associated genetic changes, is discussed with emphasis on the discrepancies emerging between tumors of foregut and of midgut origin.

  12. Extragastrointestinal Stromal Tumor (EGIST) in the abdominal wall: Case report and literature review

    PubMed Central

    Alkhatib, Loiy; Albtoush, Omar; Bataineh, Nesreen; Gharaibeh, Kamal; Matalka, Ismail; Tokuda, Yasuharu

    2011-01-01

    INTRODUCTION Gastro Intestinal Stromal Tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract (GI). GIST that arises primarily outside the GI tract is termed Extragastrointestinal Stromal Tumor (EGIST). To the best of our knowledge, few cases of EGIST in the abdominal wall were reported. PRESENTATION OF CASE We present a rare case of EGIST in the abdominal wall of a 57 year-old female patient. The asymptomatic tumor was located in the superior aspect of the left rectus abdominis muscle, measured 5.4 × cm 5.3 × cm 6.9 cm and was well circumscribed. Histological examination showed an epithelioid cell morphology. The mitotic count was 7/50 HPFs. Immunohistochemistry showed diffuse strong CD117 positivity, focal positivity for S100. The tumor was excised and the margins were free of malignancy. The patient was doing well postoperatively and was discharged on STI-571 regimen. DISCUSSION Although GIST is the most common mesenchymal tumor of the gastrointestinal tract, a case with EGIST in the abdominal wall is rare. Positive immunohistochemical staining for CD117 is a defining feature of GISTs. A great percentage of EGISTs represent a metastasis from a primary GIST. In our case, the clinical and diagnostic work-up have been proved it to be an EGIST. CONCLUSION The existing data on EGIST is insufficient to make a final conclusion regarding the malignant potential and clinicopathological factors of EGISTs that determine patient prognosis. Thus a follow-up for a long period is required. EGISTs should be kept in mind in the differential diagnosis for patients presenting with solid mass of the abdominal wall. PMID:22096744

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

    PubMed Central

    Pushparaj, Magesh; Masih, Dipti; Pulimood, Anna

    2016-01-01

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

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

    PubMed

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

    2016-02-01

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

  15. Pancreatic extra-gastrointestinal stromal tumour masquerading as a bleeding duodenal mass

    PubMed Central

    Wegge, Jacqueline; Bartholomew, David M; Burke, Leandra H; Miller, Lisa A

    2012-01-01

    We describe a 55-year-old man presenting to our institution with a gastrointestinal bleed. He was found to have a 5 cm pancreatic extra-gastrointestinal stromal tumours (EGISTs) eroding into the duodenum and ampulla of Vater. Pancreaticoduodenectomy was performed and the tumour was noted to be positive for CD117 and CD34 with six mitotic figures per 50/high-powered field. At 5 months postoperatively he is receiving treatment with imatinib and doing well. To the best of our knowledge, our patient is only the 18th case reported in the literature to date. PMID:23087281

  16. Oncogenic KRAS Regulates Tumor Cell Signaling via Stromal Reciprocation

    PubMed Central

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

    2016-01-01

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

  17. Updates in Tumor Profiling in Gastrointestinal Cancers.

    PubMed

    Perez, Kimberly; Safran, Howard P

    2015-10-01

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

  18. Stromal-dependent tumor promotion by MIF family members

    PubMed Central

    Mitchell, Robert A.; Yaddanapudi, Kavitha

    2014-01-01

    Solid tumors are composed of a heterogeneous population of cells that interact with each other and with soluble and insoluble factors that, when combined, strongly influence the relative proliferation, differentiation, motility, matrix remodeling, metabolism and microvessel density of malignant lesions. One family of soluble factors that is becoming increasingly associated with pro-tumoral phenotypes within tumor microenvironments is that of the migration inhibitory factor family which includes its namesake, MIF, and its only known family member, D-dopachrome tautomerase (D-DT). This review seeks to highlight our current understanding of the relative contributions of a variety of immune and non-immune tumor stromal cell populations and, within those contexts, will summarize the literature associated with MIF and/or D-DT. PMID:25277536

  19. Implication of Tumor Microenvironment in Chemoresistance: Tumor-Associated Stromal Cells Protect Tumor Cells from Cell Death

    PubMed Central

    Castells, Magali; Thibault, Benoît; Delord, Jean-Pierre; Couderc, Bettina

    2012-01-01

    Tumor development principally occurs following the accumulation of genetic and epigenetic alterations in tumor cells. These changes pave the way for the transformation of chemosensitive cells to chemoresistant ones by influencing the uptake, metabolism, or export of drugs at the cellular level. Numerous reports have revealed the complexity of tumors and their microenvironment with tumor cells located within a heterogeneous population of stromal cells. These stromal cells (fibroblasts, endothelial or mesothelial cells, adipocytes or adipose tissue-derived stromal cells, immune cells and bone marrow-derived stem cells) could be involved in the chemoresistance that is acquired by tumor cells via several mechanisms: (i) cell–cell and cell–matrix interactions influencing the cancer cell sensitivity to apoptosis; (ii) local release of soluble factors promoting survival and tumor growth (crosstalk between stromal and tumor cells); (iii) direct cell-cell interactions with tumor cells (crosstalk or oncologic trogocytosis); (iv) generation of specific niches within the tumor microenvironment that facilitate the acquisition of drug resistance; or (v) conversion of the cancer cells to cancer-initiating cells or cancer stem cells. This review will focus on the implication of each member of the heterogeneous population of stromal cells in conferring resistance to cytotoxins and physiological mediators of cell death. PMID:22949815

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

    ClinicalTrials.gov

    2016-08-18

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

  1. Management of gastrointestinal stromal tumours of limited size: proposals from a French panel of physicians.

    PubMed

    Landi, Bruno; Bouché, Olivier; Guimbaud, Rosine; Aparicio, Thomas; Berger, Anne; Bonvalot, Sylvie; Buecher, Bruno; Blay, Jean-Yves; Boustière, Christian; Coindre, Jean-Marie; Emile, Jean-François; Giovannini, Marc; Lecomte, Thierry; Le Cesne, Axel; Monges, Geneviève; Napoléon, Bertrand; Palazzo, Laurent; Chayvialle, Jean-Alain

    2011-12-01

    A number of guidelines on the management of gastro-intestinal stromal tumours (GISTs) have been published, mostly based on expert consensus. However, these guidelines have generally failed to address the specific problem of GISTs of limited size (i.e. those measuring a few centimetres in diameter) with which gastroenterologists are increasingly confronted. The aim of the present work was to draw up proposals for the diagnosis and treatment of GISTs measuring less than 5 cm in diameter. For this purpose, a number of practical questions were put to a panel of French experts.

  2. Gastrointestinal Stromal Tumour with Synchronous Bone Metastases: A Case Report and Literature Review

    PubMed Central

    Rochigneux, Philippe; Mescam-Mancini, Lénaig; Perrot, Delphine; Bories, Erwan; Moureau-Zabotto, Laurence; Sarran, Anthony; Guiramand, Jérôme; Bertucci, François

    2017-01-01

    Gastrointestinal stromal tumours (GISTs) are mesenchymal tumours of the digestive tract, derived from Cajal interstitial cells. Bone metastases are very rare, and there is no consensus regarding their treatment. Here, we present the unusual case of a 66-year-old man with a gastric GIST with synchronous bone and liver metastases, fully documented at the pathological and molecular levels with a KIT exon 11 mutation. After 9 months of imatinib, the scanner showed a 33% partial response of target lesions. We also review the literature and describe the characteristics, treatment, and outcome of all cases previously reported. PMID:28203166

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

    PubMed Central

    Ntourakis, Dimitrios; Mavrogenis, Georgios

    2015-01-01

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

  4. Malignant gastrointestinal neuroectodermal tumor: clinicopathologic, immunohistochemical, ultrastructural, and molecular analysis of 16 cases with a reappraisal of clear cell sarcoma-like tumors of the gastrointestinal tract.

    PubMed

    Stockman, David L; Miettinen, Markku; Suster, Saul; Spagnolo, Dominic; Dominguez-Malagon, Hugo; Hornick, Jason L; Adsay, Volkan; Chou, Pauline M; Amanuel, Benhur; Vantuinen, Peter; Zambrano, Eduardo V

    2012-06-01

    The clinical, histologic, immunophenotypic, ultrastructural, and molecular features of a distinctive gastrointestinal tumor are described. Sixteen patients, 8 women and 8 men aged 17 to 77 years (mean age, 42 y; 63% less than 40 y) presented with abdominal pain, intestinal obstruction, and an abdominal mass. Mean tumor size was 5.2 cm (range, 2.4 to 15.0 cm). The tumors arose in the small bowel (10), stomach (4), and colon (2) and were histologically characterized by a sheet-like or nested population of epithelioid or oval-to-spindle cells with small nucleoli and scattered mitoses. Five cases showed focal clearing of the cytoplasm. Scattered osteoclast-type multinucleated giant cells were present in 8 cases. The tumor cells were positive for S-100 protein, SOX10, and vimentin in 100% of cases, for CD56 in 70%, for synaptophysin in 56%, for NB84 in 50%, for NSE in 45%, and for neurofilament protein in 14% of cases. All cases tested were negative for specific melanocytic, gastrointestinal stromal tumors, epithelial, and myoid markers. Ultrastructural examination of 5 cases showed features of primitive neuroectodermal cells with clear secretory vesicles, dense-core granules, occasional gap junctions, and no evidence of melanogenesis. EWSR1 gene rearrangement was assessed by fluorescence in situ hybridization in 14 cases. Twelve cases (86%) showed split EWSR1 signal consistent with a chromosomal translocation involving EWSR1. One case showed extra intact signals, indicating that the nuclei possessed either extra copies of the EWSR1 gene or chromosome 22 polysomy. Only 1 case showed no involvement of the EWSR1 gene. Six cases demonstrated rearrangement of the partner fusion gene ATF1 (46%), and 3 showed rearrangement of CREB1 (23%); 2 cases lacked rearrangement of either partner gene. Clinical follow-up was available in 12 patients and ranged from 1.5 to 106 months. Six patients died of their tumors (mean survival, 32 mo; 83% less than 24 mo). At last follow-up, 4

  5. Spontaneous Perforation as a First Presentation of Ileal Gastrointestinal Stromal Tumour (GIST) with Synchronous Breast Sarcoma.

    PubMed

    Sharma M, Bir Kumar; Barad, Arun Kumar; Padu, Kemba; Singh K, Sridartha; Singh Th, Sudhir Chandra

    2014-05-01

    Gastrointestinal Stromal Tumours (GIST's) are the most common mesenchymal neoplasms of the gastrointestinal tract. Majority of the GISTs are asymptomatic and often diagnosis is incidental. Synchronous second malignancies have been reported in patients with GIST. We report a case of 50-year-old female presenting with features of hollow viscous perforation, found to have ileal GIST with perforations along with a synchronous breast sarcoma. GIST with spontaneous perforation as its first clinical manifestation is rare. Synchronous occurrence of an ileal GIST with a breast sarcoma is unique and deserves reporting. This case report highlights the varied nature of clinical presentation of the GIST and also stresses on the importance of extensive search for the synchronous second malignancies in the extra abdominal sites as well.

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

    ClinicalTrials.gov

    2016-04-19

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

  7. Standard of care therapy for malignant glioma and its effect on tumor and stromal cells.

    PubMed

    Jones, T S; Holland, E C

    2012-04-19

    Glioblastoma is the most common and deadly of the primary central nervous system tumors. Recent advances in molecular characterization have subdivided these tumors into at least three main groups. In addition, these tumors are cellularly complex with multiple stromal cell types contributing to the biology of the tumor and treatment response. Because essentially all glioma patients are treated with radiation, various chemotherapies and steroids, the tumor that finally kills them has been modified by these treatments. Most of the investigation of the effects of therapy on these tumors has focused on the glioma cells per se. However, despite the importance of the stromal cells in these tumors, little has been done to understand the effects of treatment on stromal cells and their contribution to disease. Understanding how current standard therapy affects the biology of the tumor and the tumor stroma may provide insight into the mechanisms that are important to the inhibition of tumor growth as well as the biology of recurrent tumors.

  8. Mixed epithelial and stromal tumor of the kidney.

    PubMed

    Adsay, N V; Eble, J N; Srigley, J R; Jones, E C; Grignon, D J

    2000-07-01

    We describe the clinicopathologic features of 12 patients with a distinctive tumor of the kidney characterized by a mixture of epithelial and stromal elements that form solid and cystic growth patterns. Similar tumors were reported previously in the literature under various names, including adult mesoblastic nephroma. All but one of the patients were women. The only man had a long history of treatment with lupron and diethylstilbesterol. Seven of the women had histories of long-term oral estrogen use of whom six had undergone total abdominal hysterectomy and bilateral salpingo-oophorectomy several years prior, and the seventh patient had been using oral contraceptives for many years. Another woman had this operation but did not receive any hormone therapy. Ages ranged from 31 to 71 years (mean, 56 yrs). Six patients presented with symptoms, including pain and infections attributable to mass effect, and in six the tumor was detected incidentally. Grossly, the tumors were well-circumscribed (mean size, 6 cm; range, 3-12 cm) and consisted of solid and cystic components, most often in equal proportions but in variable distribution. Microscopically, the spindle cell component ranged in appearance from scar-like fibrous tissue to leiomyoma-like interlacing fascicles; usually there was a mixture of both. More cellular foci reminiscent of ovarian stroma or solitary fibrous tumor were also present. No blastema was present. Epithelial elements (composed of clusters of tubules with variable lining) were scattered amidst the spindle cells, and focally transformed into large cysts lined by cells with abundant pink cytoplasm and a hobnail appearance. Immature epithelial elements typical of Wilms' tumor were not present. Muscle markers (desmin and smooth muscle actin) were positive diffusely and strongly in the spindle cells of all tumors, whereas HMB-45 and CD34 were absent. Estrogen receptors were detected in the nuclei of spindle cells in seven tumors and progesterone

  9. [Frequent allelic losses in tumor-associated stromal cells and tumor epitelium of prostate cancer].

    PubMed

    Kekeeva, T V; Popova, O P; Shegaĭ, P V; Zavalishina, L E; Andreeva, Iu Iu; Zaletaev, D V; Nemtsova, M V

    2008-01-01

    It has become increasingly clear that tumor microenvironment plays a critical role in carcinogenesis. Accumulation of genetic alterations is typical not only for cancer epithelial cells but tumor-associated fibroblasts as well. Tumor epithelia, tumor-associated stroma from prostatectomy specimens of patients with prostate cancer and cells from prostatic intraepithelial neoplasia (PIN) and adjacent stroma from males with PIN were isolated by using laser capture microdissection. Microsatellite allelotyping was evaluated using 4 highly polymorphic markers for chromosomal regions 8p22, 16q23-24 and 13q14. Incidences of alterations (loss of heterozygosity or allelic imbalance) were 48% for region 8p22, 72% for 16q23 and 37% for 13q14. The LOH frequencies in tumor-associated stroma cells were very similar. Alterations at chromosome 13q were significantly associated with advanced tumor stage, whereas AI at 16q was also associated with high Gleason score and lymph node metastasis. We find some incidences of allelic imbalance in premalignant lesions in epithelial (16-27%) and stromal (7-22%) components. Our results show that the frequencies of genetic aberrations are as high in stromal cells as in tumor cells.

  10. Biology and Treatment of Metastatic Gastrointestinal Neuroendocrine Tumors

    PubMed Central

    Strosberg, Jonathan R.; Nasir, Aejaz; Kvols, Larry

    2008-01-01

    Neuroendocrine malignancies of the gastroenteropancreatic axis include carcinoid and pancreatic endocrine tumors. These heterogeneous neoplasms arise from the enterochromaffin cells of the gastrointestinal tract and the islet cells of the pancreas. Histologically, most well-differentiated endocrine tumors consist of small, round, monomorphic cells, arranged in islands or trabeculae, with a distinct “salt-and-pepper” pattern of nuclear chromatin. Chromogranin and synaptophysin are useful as immunohistochemical markers of neuroendocrine differentiation. Other common features include the capacity to secrete peptide hormones and biogenic amines. A relatively indolent growth rate is characteristic of most gastrointestinal neuroendocrine tumors, with the exception of poorly differentiated tumors which are usually aggressive. Treatment strategies are designed to limit tumor progression and palliate hormonal syndromes. This article reviews the diverse biologic characteristics of gastrointestinal neuroendocrine tumors and current treatment options for metastatic disease. PMID:19259290

  11. Role of imatinib in the management of early, operable, and advanced GI stromal tumors (GISTs)

    PubMed Central

    Vetto, John T

    2009-01-01

    Gastrointestinal stromal tumors (GISTs), the most common sarcoma of the GI tract, have unique kinase mutations that serve as targets for medical therapy. This article reviews the data supporting the use of the tyrosine kinase inhibitor (TKI) imatinib in GIST patients, and how this treatment should be combined with surgical resection (when possible) to optimize patient outcomes. Although surgical resection remains the mainstay of treatment for these tumors, patients with resected GISTs have high relapse rates that can be reduced by 1 year of adjuvant imatinib. Data also support the use of imatinib for patients with recurrent or unresectable GIST. In these patients the drug should be continued until progression, intolerance, or the patients are rendered resectable. Patients with advanced GIST who are successfully resected after imatinib treatment should be placed back on imatinib postoperatively. Patients who develop generalized progression (progression at 2 or more sites) on imatinib should move to other treatments, such as newer TKIs or other targeted approaches currently under study. Genotyping of the tumor should be considered in all pediatric GISTs and high risk adult GISTs, especially if there is progression on imatinib. Quality of life and the cost/benefit of new therapies are important issues for further study in patients with GIST. PMID:20616902

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

    PubMed Central

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

    2014-01-01

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

  13. Progressive Enrichment of Stemness Features and Tumor Stromal Alterations in Multistep Hepatocarcinogenesis

    PubMed Central

    Rhee, Hyungjin; Kim, Haeryoung; Ahn, Ei Yong; Choi, Jin Sub; Roncalli, Massimo; Park, Young Nyun

    2017-01-01

    Cancer stem cells (CSCs), a subset of tumor cells, contribute to an aggressive biological behavior, which is also affected by the tumor stroma. Despite the role of CSCs and the tumor stroma in hepatocellular carcinoma (HCC), features of stemness have not yet been studied in relation to tumor stromal alterations in multistep hepatocarcinogenesis. We investigated the expression status of stemness markers and tumor stromal changes in B viral carcinogenesis, which is the main etiology of HCC in Asia. Stemness features of tumoral hepatocytes (EpCAM, K19, Oct3/4, c-KIT, c-MET, and CD133), and tumor stromal cells expressing α-smooth muscle actin (α-SMA), CD68, CD163, and IL-6 were analyzed in 36 low grade dysplastic nodules (DNs), 48 high grade DNs, 30 early HCCs (eHCCs), and 51 progressed HCCs (pHCCs) by immunohistochemistry or real-time PCR. Stemness features (EpCAM and K19 in particular) were progressively acquired during hepatocarcinogenesis in combination with enrichment of stromal cells (CAFs, TAMs, IL-6+ cells). Stemness features were seen sporadically in DNs, more consistent in eHCCs, and peaked in pHCCs. Likewise, stromal cells were discernable in DNs, showed up as consistent cell densities in eHCCs and peaked in pHCCs. The stemness features and tumor stromal alterations also peaked in less differentiated or larger HCCs. In conclusion, progression of B viral multistep hepatocarcinogenesis is characterized by an enrichment of stemness features of neoplastic hepatocytes and a parallel alteration of the tumor stroma. The modulation of neoplastic hepatocytes and stromal cells was at low levels in precancerous lesions (DNs), consistently increased in incipient cancer (eHCCs) and peaked in pHCCs. Thus, in B viral hepatocarcinogenesis, interactions between CSCs and the tumor stroma, although starting early, seem to play a major role in tumor progression. PMID:28114366

  14. Progressive Enrichment of Stemness Features and Tumor Stromal Alterations in Multistep Hepatocarcinogenesis.

    PubMed

    Yoo, Jeong Eun; Kim, Young-Joo; Rhee, Hyungjin; Kim, Haeryoung; Ahn, Ei Yong; Choi, Jin Sub; Roncalli, Massimo; Park, Young Nyun

    2017-01-01

    Cancer stem cells (CSCs), a subset of tumor cells, contribute to an aggressive biological behavior, which is also affected by the tumor stroma. Despite the role of CSCs and the tumor stroma in hepatocellular carcinoma (HCC), features of stemness have not yet been studied in relation to tumor stromal alterations in multistep hepatocarcinogenesis. We investigated the expression status of stemness markers and tumor stromal changes in B viral carcinogenesis, which is the main etiology of HCC in Asia. Stemness features of tumoral hepatocytes (EpCAM, K19, Oct3/4, c-KIT, c-MET, and CD133), and tumor stromal cells expressing α-smooth muscle actin (α-SMA), CD68, CD163, and IL-6 were analyzed in 36 low grade dysplastic nodules (DNs), 48 high grade DNs, 30 early HCCs (eHCCs), and 51 progressed HCCs (pHCCs) by immunohistochemistry or real-time PCR. Stemness features (EpCAM and K19 in particular) were progressively acquired during hepatocarcinogenesis in combination with enrichment of stromal cells (CAFs, TAMs, IL-6+ cells). Stemness features were seen sporadically in DNs, more consistent in eHCCs, and peaked in pHCCs. Likewise, stromal cells were discernable in DNs, showed up as consistent cell densities in eHCCs and peaked in pHCCs. The stemness features and tumor stromal alterations also peaked in less differentiated or larger HCCs. In conclusion, progression of B viral multistep hepatocarcinogenesis is characterized by an enrichment of stemness features of neoplastic hepatocytes and a parallel alteration of the tumor stroma. The modulation of neoplastic hepatocytes and stromal cells was at low levels in precancerous lesions (DNs), consistently increased in incipient cancer (eHCCs) and peaked in pHCCs. Thus, in B viral hepatocarcinogenesis, interactions between CSCs and the tumor stroma, although starting early, seem to play a major role in tumor progression.

  15. Stromal prostatic sarcoma: a rare tumor with rare clinical and imaging presentation

    PubMed Central

    Rojas-Jiménez, Anamaría; Otero-Garcia, Milagros; Mateos-Martin, Alejandro

    2013-01-01

    Adult prostatic stromal sarcoma is a rare malignant tumor. The main presenting symptom is urinary retention secondary to bladder outlet obstruction. Prostatic Specific Antigen level can be normal. Imaging features show a prostate mass with or without pelvic organ invasion depending on the aggressiveness of the tumor. We present a patient with prostatic stromal sarcoma who debuted with urinary obstruction, leukocytosis and neutrophilia, prostate enlargement, and hypodense prostate areas on CT images, simulating prostatitis with abscess formation. PMID:24421945

  16. Do We Know What Causes Gastrointestinal Stromal Tumors?

    MedlinePlus

    ... gene is found in all cells of the body. It directs the cell to make a protein called KIT, which causes the cell to grow and divide. Usually the c-kit gene in interstitial cells of Cajal (ICCs) is inactive. It is only active if ...

  17. [Medical treatment for gastrointestinal stromal tumor (GIST) in Japan].

    PubMed

    Sato, Atsushi; Hamada, Kazuyuki; Imataka, Hiromi

    2012-05-01

    To facilitate an optimal diagnosis and treatment of GIST in Japan, the Japanese Clinical Practice Guideline for GIST was proposed by the GIST Guideline Subcommittee. Multidisciplinary treatment planning is needed(involving pathologists, radiologists, surgeons and medical oncologists)for patients with GIST. Medical treatment is usually selected for unresectable GIST, metastatic GIST at the initial examination, and recurrent GIST. Imatinib is strongly recommended for patients with KIT-positive GIST; the standard dose of imatinib mesylate(Glivec)is 400 mg/day. For patients with imatinib-resistant GIST, Sunitinib (Sutent)is now approved in Japan and is covered by medical insurance. However, high-dose imatinib(>400mg/day)has not yet been approved in Japan.

  18. Accomplishments in 2008 in the Management of Gastrointestinal Stromal Tumors

    PubMed Central

    Renouf, Daniel; Blay, Jean-Yves; Blanke, Charles

    2009-01-01

    SUMMARY Overview of the Disease ProcessIncidencePrognosisPredictive MarkersCurrent General Therapy Standards in North America and EuropeLocalized or Potentially Resectable DiseaseUnresectable or Metastatic DiseaseAccomplishments During the YearTherapySurgical Issues and Perioperative TherapyImatinibSunitinibNew DrugsBiomarkersBasic and Other Translational ScienceWhat Needs to Be DoneFuture DirectionsComments on ResearchObstacles to Progress PMID:20011569

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

    PubMed Central

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

    2016-01-01

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

  20. Endosonographic features predictive of benign and malignant gastrointestinal stromal cell tumours

    PubMed Central

    Palazzo, L; Landi, B; Cellier, C; Cuillerier, E; Roseau, G; Barbier, J

    2000-01-01

    BACKGROUND/AIM—Some endoscopic ultrasonographic (EUS) features have been reported to be suggestive of malignancy in gastrointestinal stromal cell tumours (SCTs). The aim of this study was to assess the predictive value of these features for malignancy.
METHODS—A total of 56 histologically proven cases of SCT studied by EUS between 1989 and 1996 were reviewed. There were 42 gastric tumours, 12 oesophageal tumours, and two rectal tumours. The tumours were divided into two groups: (a) benign SCT, comprising benign leiomyoma (n = 34); (b) malignant or borderline SCT (n = 22), comprising leiomyosarcoma (n = 9), leiomyoblastoma (n = 9), and leiomyoma of uncertain malignant potential (n = 4). The main EUS features recorded were tumour size, ulceration, echo pattern, cystic spaces, extraluminal margins, and lymph nodes with a malignant pattern. The two groups were compared by univariate and multivariate analysis.
RESULTS—Irregular extraluminal margins, cystic spaces, and lymph nodes with a malignant pattern were most predictive of malignant or borderline SCT. Pairwise combinations of the three features had a specificity and positive predictive value of 100% for malignant or borderline SCT, but a sensitivity of only 23%. The presence of at least one of these three criteria had 91% sensitivity, 88% specificity, and 83% predictive positive value. In multivariate analysis, cystic spaces and irregular margins were the only two features independently predictive of malignant potential. The features most predictive of benign SCTs were regular margins, tumour size ⩽30 mm, and a homogeneous echo pattern. When the three features were combined, histology confirmed a benign SCT in all cases.
CONCLUSIONS—The combined presence of two out of three EUS features (irregular extraluminal margins, cystic spaces, and lymph nodes with a malignant pattern) had a positive predictive value of 100% for malignant or borderline gastrointestinal SCT. Tumours less than 30

  1. Endoscopic full-thickness resection and laparoscopic surgery for treatment of gastric stromal tumors

    PubMed Central

    Huang, Liu-Ye; Cui, Jun; Wu, Cheng-Rong; Zhang, Bo; Jiang, Li-Xin; Xian, Xiang-Shu; Lin, Shu-Juan; Xu, Ning; Cao, Xiao-Ling; Wang, Zhi-Hua

    2014-01-01

    AIM: To assess the effectiveness of endoscopic full-thickness resection (EFR) and laparoscopic surgery in the treatment of gastric stromal tumors arising from the muscularis propria. METHODS: Out of 62 gastric stromal tumors arising from the muscularis propria, each > 1.5 cm in diameter, 32 were removed by EFR, and 30 were removed by laparoscopic surgery. The tumor expression of CD34, CD117, Dog-1, S-100, and SMA was assessed immunohistochemically. The operative time, complete resection rate, length of hospital stay, incidence of complications, and recurrence rate were compared between the two groups. Continuous data were compared using independent samples t-tests, and categorical data were compared using χ2 tests. RESULTS: The 32 gastric stromal tumors treated by EFR and the 30 treated by laparoscopic surgery showed similar operative time [20-155 min (mean, 78.5 ± 30.1 min) vs 50-120 min (mean, 80.9 ± 46.7 min), P > 0.05], complete resection rate (100% vs 93.3%, P > 0.05), and length of hospital stay [4-10 d (mean, 5.9 ± 1.4 d) vs 4-19 d (mean, 8.9 ± 3.2 d), P >0.05]. None of the patients treated by EFR experienced complications, whereas two patients treated by laparoscopy required a conversion to laparotomy, and one patient had postoperative gastroparesis. No recurrences were observed in either group. Immunohistochemical staining showed that of the 62 gastric stromal tumors diagnosed by gastroscopy and endoscopic ultrasound, six were leiomyomas (SMA-positive), one was a schwannoglioma (S-100 positive), and the remaining 55 were stromal tumors. CONCLUSION: Some gastric stromal tumors arising from the muscularis propria can be completely removed by EFR. EFR could likely replace surgical or laparoscopic procedures for the removal of gastric stromal tumors. PMID:25009400

  2. Treatment of Gastrointestinal Carcinoid Tumors by Stage

    MedlinePlus

    ... carcinoid tumors of the stomach. Patients with these conditions who have stomach carcinoid tumors are treated differently from patients without these conditions. Type 1: Patients with high gastrin levels but low levels of stomach acid are said to have type 1 tumors. ...

  3. Can Gastrointestinal Carcinoid Tumors Be Found Early?

    MedlinePlus

    ... may also be found when parts of the gastrointestinal system are removed to treat other diseases. For example, a person with stomach pain or bleeding may have a test called an upper endoscopy to look for an ulcer. In this test, the doctor looks at the stomach ... Medical Review: February 26, 2015 ...

  4. Esophageal subepithelial lesion diagnosed as malignant gastrointestinal neuroectodermal tumor.

    PubMed

    Kim, Sung Bum; Lee, Si Hyung; Gu, Mi Jin

    2015-05-14

    A 21-year-old male visited our hospital with a complaint of aggravating dysphagia and odynophagia for a few days. Esophagogastroduodenoscopy showed huge bulging mucosa with an intact surface causing luminal narrowing at 35 cm from the incisor teeth. Endoscopic ultrasonography showed an about 35 mm sized irregular margined in-homogenous hypoechoic lesion with an obscure layer of origin. Endoscopic ultrasonography fine needle aspiration revealed spindle cell proliferation without immunoreactivity for CD117, SMA, and cytokeratin. The patient underwent excision of the subepithelial lesion at the distal esophagus. On pathologic examination of the specimen, the tumor was composed of short fascicles of oval to spindle cells with eosinophilic and clear cytoplasm and vesicular nuclei. The tumor cells were positive for S-100 and SOX10 and negative for CD117, SMA, HMB-45, melan-A, cytokeratin, and CD99. The split-apart signal was detected in EWSR1 on FISH, suggesting a malignant gastrointestinal neuroectodermal tumor. At the time of writing, the patient is on radiation therapy at the operated site of esophagus and doing well, with no recurrence for three months. Malignant gastrointestinal neuroectodermal tumor is a rare gastrointestinal tumor with features of clear cell sarcoma, without melanocytic differentiation, and shows a poor prognosis. This is the first reported case of malignant gastrointestinal neuroectodermal tumor arising as subepithelial lesion in the esophagus.

  5. Molecular predictive markers in tumors of the gastrointestinal tract

    PubMed Central

    Papadopoulou, Eirini; Metaxa-Mariatou, Vasiliki; Tsaousis, Georgios; Tsoulos, Nikolaos; Tsirigoti, Angeliki; Efstathiadou, Chrisoula; Apessos, Angela; Agiannitopoulos, Konstantinos; Pepe, Georgia; Bourkoula, Eugenia; Nasioulas, George

    2016-01-01

    Gastrointestinal malignancies are among the leading causes of cancer-related deaths worldwide. Like all human malignancies they are characterized by accumulation of mutations which lead to inactivation of tumor suppressor genes or activation of oncogenes. Advances in Molecular Biology techniques have allowed for more accurate analysis of tumors’ genetic profiling using new breakthrough technologies such as next generation sequencing (NGS), leading to the development of targeted therapeutical approaches based upon biomarker-selection. During the last 10 years tremendous advances in the development of targeted therapies for patients with advanced cancer have been made, thus various targeted agents, associated with predictive biomarkers, have been developed or are in development for the treatment of patients with gastrointestinal cancer patients. This review summarizes the advances in the field of molecular biomarkers in tumors of the gastrointestinal tract, with focus on the available NGS platforms that enable comprehensive tumor molecular profile analysis. PMID:27895815

  6. A Survey of DICER1 Hotspot Mutations in Ovarian and Testicular Sex Cord-Stromal Tumors

    PubMed Central

    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

    2015-01-01

    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 2 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 occur

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

    PubMed

    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

  8. Diagnostic procedures for submucosal tumors in the gastrointestinal tract

    PubMed Central

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

    2007-01-01

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

  9. Primary gastrointestinal stromal tumour of the ileum pre-operatively diagnosed as an abdominal abscess

    PubMed Central

    Rubini, Patrizia; Tartamella, Francesco

    2016-01-01

    The present case report described the acute presentation, diagnosis and management of a primary gastrointestinal stromal tumour (GIST) of the ileum. A male patient (age, 51 years) was admitted to Maggiore Hospital (Parma, Italy) due to presenting with fever, dysuria and lower abdominal pain. Ultrasonography and computed tomography showed a 7,5×5,5-cm pelvic mass containing air and purulent fluid indicative of an intraperitoneal abscess. The patient was subjected to diagnostic laparoscopy, which revealed a huge, soft cystic mass arising from the small bowel. The procedure was then converted to an open exploration through a midline incision. Ileal resection including a Meckel's diverticulum was performed. Macroscopic examination revealed that the cystic mass was filled with a large amount of pus, probably due to communication between the tumour mass and the small bowel lumen. In fact, the surgical specimen showed enteric leakage from the ileal mucosal ulcer into the tumour mass. Histopathology and immunohistochemistry of the abscess wall identified a spindle-cell mesenchymal-type, c-KIT-positive neoplasm. The post-operative course was uneventful and adjuvant imatinib mesylate was administered for 1 year. Follow-up by computed tomography demonstrated no tumour recurrence at 72 months after surgery. PMID:27900093

  10. Primary omental gastrointestinal stromal tumour (GIST) presenting with a large abdominal mass and spontaneous haemoperitoneum.

    PubMed

    Seow-En, Isaac; Seow-Choen, Francis; Lim, Tony Kiat Hon; Leow, Wei Qiang

    2014-11-03

    A 60-year-old Indonesian woman presented with a 9-day history of increasing abdominal distension, pain and tiredness. Physical examination revealed significant pallor with a palpable mass in the abdomen. CT of the abdomen reported a 22 cm complex mass in the peritoneal cavity with free intra-abdominal fluid. Laboratory results showed anaemia with a raised serum CA 125 level. At laparotomy a large haemorrhagic tumour with blood filled cystic cavities was found attached to both greater omentum and the transverse mesocolon with 2.2 L of blood in the peritoneal cavity. There was no invasion of any part of the stomach or intestines and there were no metastases seen. Histopathology of the resected specimen was consistent with that of a gastrointestinal stromal tumour arising from the omentum. Immunohistochemical studies revealed the tumour to be strongly positive for discovered on GIST-1 (DOG1) but negative for both CD117 and CD34. Platelet-derived growth factor receptor α (PDGFRA) exon 18 mutation D842V was detected.

  11. Duration of adjuvant treatment following radical resection of metastases from gastrointestinal stromal tumours

    PubMed Central

    NANNINI, MARGHERITA; PANTALEO, MARIA ABBONDANZA; MALEDDU, ALESSANDRA; SAPONARA, MARISTELLA; MANDRIOLI, ANNA; LOLLI, CRISTIAN; PALLOTTI, MARIA CATERINA; GATTO, LIDIA; SANTINI, DONATELLA; PATERINI, PAOLA; DI SCIOSCIO, VALERIO; CATENA, FAUSTO; FUSAROLI, PIETRO; PINNA, ANTONIO DANIELE; DEI TOS, ANGELO PAOLO; BIASCO, GUIDO

    2011-01-01

    Large-scale studies have demonstrated that continuative treatment in advanced and adjuvant settings results in a gain-of-survival. However, the discontinuation, and the duration of treatment in disease-free patients who have undergone radical surgical resection of metastases from gastrointestinal stromal tumours (GISTs) have yet to be evaluated. We retrospectively reviewed 40 patients with advanced and recurrent GIST, included in our GIST database, focusing on patients (5 males and 2 females; median age 56 years) who continued medical treatment following radical surgical resection of metastatic lesions. Seven out of 40 patients underwent surgery and continued medical treatment following radical surgical resection of metastatic lesions. The duration of adjuvant therapy was 3, 12, 16, 24, 35, 37 and 52 months, respectively, with a median of 26 months. No patients discontinued therapy and all were disease-free at the final CT-scan evaluation. Considering that the discontinuation of imatinib in responding patients with advanced GIST (even in complete remission) results in a rapid high risk of progression, and a short adjuvant therapy results in a shorter disease-free and overall survival in high-risk GIST patients, it is also likely that treatment should not be discontinued in this setting. However, large-scale studies are required to better assess the optimal duration of treatment, particularly after 5 years, by focusing on the identification of predictive factors for the selection of patients who may benefit from a prolonged or lifelong imatinib treatment. PMID:22740975

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

    PubMed

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

    2016-01-01

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

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

    PubMed Central

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

    2016-01-01

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

  14. Early diagnosis and treatment of gastrointestinal neuroendocrine tumors

    PubMed Central

    Shen, Hong; Yu, Zhuo; Zhao, Jing; Li, Xiu-Zhen; Pan, Wen-Sheng

    2016-01-01

    The aim of the present retrospective analysis on the macroscopic appearance and pathological characteristics of gastrointestinal neuroendocrine tumors (NETs) was to investigate methods for their early diagnosis and treatment. A total of 78 patients were divided into submucosal NET and deeper invasion NET groups, according to the depth of tumor invasion exhibited by the patients. The clinicopathological characteristics and survival time of the NET patients were analyzed and compared. The pathological characteristics of the submucosal NETs group were investigated according to the diameter of the tumor (≤5.0 mm, 5.1–10.0 mm or >10.0 mm). The depth of invasion at diagnosis was observed to significantly correlate with histopathological classification, diameter of the tumor, macroscopic appearance, growth pattern, lymphatic-vascular involvement, lymph node (LN) metastasis and distant metastasis. In the submucosal NETs group, high-grade tumors with lymphatic or venule invasion and distant metastasis were associated with an increased risk of nodal metastases. In patients with minute tumors (≤5.0 mm), no lymphatic-vascular involvement, LN or distant metastasis was observed. By contrast, patients with tumors measuring 5.1–10.0 mm in diameter exhibited high lymphatic-vascular involvement and LN metastasis rates (46.2 and 30.8%, respectively). Survival time was significantly longer in patients with submucosal NETs compared with deeper invasion NETs and in patients with NET G1 and NET G2 compared with NEC. The results of the present study indicate that gastrointestinal submucosal NETs are closely associated with a slightly elevated macroscopic type, low-grade tumors and a small diameter. These features may contribute to early diagnosis of gastrointestinal NETs. Therefore, a tumor diameter of <5.0 mm, with slightly elevated macroscopic appearance may indicate an absolute requirement for endoscopic resection, while tumors measuring 5.1–10.0 mm in diameter must be

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

    SciTech Connect

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

    2008-02-01

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

  16. Chronic therapy in gastrointestinal stromal tumours (GISTs): the big gap between theory and practice.

    PubMed

    Saponara, Maristella; Pantaleo, Maria Abbondanza; Nannini, Margherita; Biasco, Guido

    2012-12-01

    The advent of imatinib mesilate, an oral target therapy, has dramatically changed the natural history of gastrointestinal stromal tumours (GISTs). This rare neoplasm has become the paradigm of targeted therapies in solid tumours, also introducing a home-based cure concept in oncology. However, it should be retained that oral drug administration entails new and relevant management problems. Multiple studies have demonstrated the efficacy of imatinib in GISTs associated with a good toxicity profile. However, the efficacy of imatinib, according to its mechanism of action and pharmacokinetics, is closely related to daily assumption. No interruption or "jerky" assumption is permitted in order to avoid efficacy loss. Thus, the issue of treatment adherence is crucial for a successful strategy and should not be overlooked. We think that dealing with the problem means assessing a wide spectrum of not only clinical and general but also psychological and individual aspects. Furthermore, both patient and family should play an active role in the "cure process" and physicians should reduce the distance separating them from their patients due to home-based target therapy, promoting communication and consolidation of a trust-based physician-patient relationship. Several advantages have been introduced by oral target therapies in oncology. However, chronic drug administration, even if generally well tolerated, when prolonged for an undetermined time could heavily impact on patients' quality of life. This could induce non-prescribed drug suspension, with negative impact on disease control. More studies would be necessary in order to detect real patients' adherence, to correlate drug assumption with clinical outcome and to optimize imatinib treatment strategy.

  17. Laparoscopic management of gastrointestinal stromal tumours: review at a Canadian centre

    PubMed Central

    Daigle, Carl; Meneghetti, Adam T.; Lam, Jasmine; Panton, Ormond N.M.

    2012-01-01

    Background Laparoscopic wedge resection has been widely accepted for small benign gastric tumours. Large gastrointestinal stromal tumours (GISTs), however, can be difficult to manipulate laparoscopically and are at risk for capsule disruption, which can then result in peritoneal seeding. Some authors have suggested that large GISTs (> 8 cm) are best approached using an open technique. However, there has been no consensus as to what the cut-off size should be. We conducted one of the largest Canadian series to date to assess outcomes and follow-up of the laparoscopic management of GISTs. Methods All patients with gastric GISTs presenting to Vancouver General Hospital and University of British Columbia Hospital between 2000 and 2008 were reviewed. Most lesions were resected using a wedge technique with closure of the stomach facilitated by an endoscopic linear stapling device. Results In all, 23 patients presented with GISTs; 19 patients underwent laparoscopic resection and, of these, 15 had a purely laparoscopic operation and 4 had a hand-assisted laparoscopic resection. Mean tumour size was 3.2 cm, with the largest tumour measuring 6.8 cm. There were no episodes of tumour rupture or spillage and no major intraoperative complications. All margins were negative. Mean follow-up was 13.3 (range 1–78) months. There was no evidence of recurrence or metastasis. Conclusion The laparoscopic management of gastric GISTs is safe and effective with short hospital stays and good results over a mean follow-up of 13.3 months. We believe that it should be the preferred technique offered to patients. PMID:22269221

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

    ClinicalTrials.gov

    2016-03-16

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

  19. Nuclear Localization of β-Catenin in Sertoli Cell Tumors and Other Sex Cord-Stromal Tumors of the Testis: An Immunohistochemical Study of 87 Cases.

    PubMed

    Zhang, Chen; Ulbright, Thomas M

    2015-10-01

    The diagnosis and subclassification of Sertoli cell tumors (SCT) of the testis are often challenging to general surgical pathologists because of the rarity of the tumors. Immunohistochemical study to date has limited diagnostic value. Nuclear localization of β-catenin, which correlated closely with CTNNB1 gene mutation, was recently reported in SCTs. We investigated the utility of β-catenin nuclear localization in diagnosing SCTs and differentiating them from other testicular sex cord-stromal tumors. Immunohistochemical staining for β-catenin was evaluated in 87 cases of testicular sex cord-stromal tumor: 33 SCTs, not otherwise specified (SCT-NOS) (15 with benign and 18 with malignant features), 10 sclerosing SCTs (SSCT), 5 large cell calcifying SCTs (LCCSCT), 6 Sertoli-stromal cell tumors, 10 Leydig cell tumors, 7 juvenile granulosa cell tumors, 4 adult granulosa cell tumors, and 12 sex cord-stromal tumors, unclassified. Twenty-one of 33 (64%) SCT-NOS, 6 of 10 (60%) SSCTs, and 4 of 6 (67%) Sertoli-stromal cell tumors showed strong, diffuse β-catenin nuclear staining. Nuclear β-catenin positivity was more frequent in SCTs-NOS with benign features than in those with malignant features (93% and 39%, respectively, P=0.13) and, in the Sertoli-stromal cell tumors, occurred only in the Sertoli component. All 5 LCCSCTs and all other types of sex cord-stromal tumor were negative for β-catenin nuclear staining. In conclusion, SCT-NOS and SSCT frequently show β-catenin nuclear localization. Positive nuclear staining of β-catenin is specific for SCT-NOS, SSCT, and Sertoli-stromal cell tumor among testicular sex cord-stromal tumors but has limited sensitivity (63%) in this group. The similar reactivity of SCT-NOS and SSCT provides additional support that these 2 variants are not distinct entities.

  20. Breast tumor and stromal cell responses to TGF-β and hypoxia in matrix deposition

    PubMed Central

    Curran, Colleen S.; Keely, Patricia J

    2012-01-01

    The components that comprise the extracellular matrix (ECM) are integral to normal tissue homeostasis as well as the development and progression of breast tumors. The secretion, construction, and remodeling of the ECM are each regulated by a complex interplay between tumor cells, fibroblasts and macrophages. Transforming growth factor-β (TGF-β) is an essential molecule in regulating the cellular production of ECM molecules and the adhesive interactions of cells with the ECM. Additionally, hypoxic cell signals, initiated by oxygen deprivation, additional metabolic factors or receptor activation, are associated with ECM formation and the progression of breast cancer. Both TGF-β and hypoxic cell signals are implicated in the functional and morphological changes of cancer-associated-fibroblasts and tumor-associated-macrophages. Moreover, the enhanced recruitment of tumor and stromal cells in response to hypoxia-induced chemokines leads to increased ECM deposition and remodeling, increased blood vessel formation, and enhanced tumor migration. Thus, elucidation of the collaborative networks between tumor and stromal cells in response to the combined signals of TGF-β and hypoxia may yield insight into treatment parameters that target both tumor and stromal cells. PMID:23262216

  1. Periductal Stromal Tumor of the Breast: A Case Report and Review of the Literature

    PubMed Central

    Askan, Gökçe; Arıbal, Erkin; Ak, Gamze; Kaya, Handan

    2016-01-01

    We present a woman aged 50 years who underwent a Tru-cut biopsy for a BI-RADS 4 lesion on her right breast and received a histopathology diagnosis of a fibroadenoma. In her one year follow-up, the lesion had progressed and she underwent an excisional biopsy. Her final diagnosis was a periductal stromal tumor. Periductal stromal tumor is an extremely rare and different entity from phylloides tumor, which makes appropriate diagnosis difficult in Tru-cut biopsy and care should be taken. Lesion progression of should require a re-biopsy. Their tendency to recur warrants follow-up. We believe that radiologic, pathologic, and clinical correlation is key in decision-making and diagnosis of these tumors. PMID:28331749

  2. Tumor-Activated Mesenchymal Stromal Cells Promote Osteosarcoma Stemness and Migratory Potential via IL-6 Secretion

    PubMed Central

    Cortini, Margherita; Massa, Annamaria; Avnet, Sofia; Bonuccelli, Gloria; Baldini, Nicola

    2016-01-01

    Osteosarcoma (OS) is an aggressive bone malignancy with a high relapse rate despite combined treatment with surgery and multiagent chemotherapy. As for other cancers, OS-associated microenvironment may contribute to tumor initiation, growth, and metastasis. We consider mesenchymal stromal cells (MSC) as a relevant cellular component of OS microenvironment, and have previously found that the interaction between MSC and tumor cells is bidirectional: tumor cells can modulate their peripheral environment that in turn becomes more favorable to tumor growth through metabolic reprogramming. Here, we determined the effects of MSC on OS stemness and migration, two major features associated with recurrence and chemoresistance. The presence of stromal cells enhanced the number of floating spheres enriched in cancer stem cells (CSC) of the OS cell population. Furthermore, the co-culturing with MSC stimulated the migratory capacity of OS via TGFβ1 and IL-6 secretion, and the neutralizing antibody anti-IL-6 impaired this effect. Thus, stromal cells in combination with OS spheres exploit a vicious cycle where the presence of CSC stimulates mesenchymal cytokine secretion, which in turn increases stemness, proliferation, migration, and metastatic potential of CSC, also through the increase of expression of adhesion molecules like ICAM-1. Altogether, our data corroborate the concept that a comprehensive knowledge of the interplay between tumor and stroma that also includes the stem-like fraction of tumor cells is needed to develop novel and effective anti-cancer therapies. PMID:27851822

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

    PubMed Central

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

    2011-01-01

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

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

    PubMed

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

    2015-01-01

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

  5. Differential gene expression in stromal cells of human giant cell tumor of bone.

    PubMed

    Wuelling, M; Delling, G; Kaiser, E

    2004-12-01

    Giant cell tumor (GCT) offers a unique model for the hematopoietic-stromal cell interaction in human bone marrow. Evidence has been presented that GCT stromal cells (GCTSCs) promote accumulation, size and activity of the giant cells. Although GCTSCs are considered the neoplastic component of GCT, little is known about their genetic basis and, to date, a tumor-specific gene expression pattern has not been characterized. Mesenchymal stem cells (MSCs) have been identified as the origin of the GCT neoplastic stromal cell. Using state of the art array technology, expression profiling was applied to enriched stromal cell populations from five different GCTs and two primary MSCs as controls. Of the 29 differentially expressed genes found, 25 showed an increased expression. Differential mRNA expression was verified by real-time polymerase chain reaction analysis of 10 selected genes, supporting the validity of cDNA arrays as a tool to identify tumor-related genes in GCTSCs. Increased expression of two oncogenes, JUN and NME2, was substantiated at the protein level, utilizing immunohistochemical evaluation of GCT sections and Western-blot analysis. Increased phosphorylation of JUN Ser-63 was also found.

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

    PubMed

    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.

  7. Solid tumor therapy by selectively targeting stromal endothelial cells

    PubMed Central

    Liu, Shihui; Liu, Jie; Ma, Qian; Cao, Liu; Fattah, Rasem J.; Yu, Zuxi; Bugge, Thomas H.; Finkel, Toren; Leppla, Stephen H.

    2016-01-01

    Engineered tumor-targeted anthrax lethal toxin proteins have been shown to strongly suppress growth of solid tumors in mice. These toxins work through the native toxin receptors tumor endothelium marker-8 and capillary morphogenesis protein-2 (CMG2), which, in other contexts, have been described as markers of tumor endothelium. We found that neither receptor is required for tumor growth. We further demonstrate that tumor cells, which are resistant to the toxin when grown in vitro, become highly sensitive when implanted in mice. Using a range of tissue-specific loss-of-function and gain-of-function genetic models, we determined that this in vivo toxin sensitivity requires CMG2 expression on host-derived tumor endothelial cells. Notably, engineered toxins were shown to suppress the proliferation of isolated tumor endothelial cells. Finally, we demonstrate that administering an immunosuppressive regimen allows animals to receive multiple toxin dosages and thereby produces a strong and durable antitumor effect. The ability to give repeated doses of toxins, coupled with the specific targeting of tumor endothelial cells, suggests that our strategy should be efficacious for a wide range of solid tumors. PMID:27357689

  8. Using polarization-sensitive optical coherence tomography to identify tumor stromal fibrosis and increase tumor biopsy yield (Conference Presentation)

    NASA Astrophysics Data System (ADS)

    Hariri, Lida P.; Adams, David C.; Miller, Alyssa J.; Mino-Kenudson, Mari; Suter, Melissa J.

    2016-03-01

    Tissue biopsy is the principal method used to diagnose tumors in a variety of organ systems. It is essential to maximize tumor yield in biopsy specimens for both clinical diagnostic and research purposes. This is particularly important in tumors where additional tissue is needed for molecular analysis to identify patients who would benefit from mutation-specific targeted therapy, such as in lung carcinomas. Inadvertent sampling of fibrotic stroma within tumor nodules contaminates biopsies, decreases tumor yield, and can impede diagnosis. The ability to assess tumor composition and guide biopsy site selection in real time is likely to improve diagnostic yield. Polarization sensitive OCT (PS-OCT) measures birefringence in organized tissues, such as collagen, and could be used to distinguish tumor from fibrosis. In this study, PS-OCT was obtained in 65 lung nodule samples from surgical resection specimens containing varying ratios of tumor and fibrosis. PS-OCT was obtained with either a custom-built helical scanning catheter (0.8 or 1.6mm in diameter) or a dual-axis bench top scanner. Strong birefringence was observed in nodules containing dense fibrosis, with no birefringence in adjacent regions of tumor. Tumors admixed with early, loosely-organized collagen demonstrated mild-to-moderate birefringence, and tumors with little collagen content showed little to no birefringent signal. PS-OCT provides significant insights into tumor nodule composition, and has potential to differentiate tumor from stromal fibrosis during biopsy site selection to increase diagnostic tumor yield.

  9. Plexiform Fibrohistiocytic Tumor on the Ear: Case Report and Immunohistochemical Investigation of Stromal Factor

    PubMed Central

    Shido, Kosuke; Fujimura, Taku; Kakizaki, Aya; Furudate, Sadanori; Asano, Masayuki; Aiba, Setsuya

    2016-01-01

    Plexiform fibrohistiocytic tumor (PFT) is a rare mesenchymal neoplasm of intermediate malignant potential with a high local recurrence rate. In this report, we describe a case of PFT on the ear, which showed a dense deposition of periostin (POSTN) in the stromal areas of the tumor. In addition, dense infiltration of CD163+CD206– tumor-associated macrophages (TAMs) was detected in the same areas as POSTN. Since POSTN was previously reported to possess immunomodulatory effects on TAMs, our present report suggested the significance of the POSTN/TAMs axis in the progression of PFT. PMID:27293390

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

    PubMed

    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

  11. Ovarian stromal tumor with minor sex cord elements with coexistent endometrial carcinoma.

    PubMed

    Kumar, Sunesh; Mathur, Sandeep; Subbaiah, Murali; Singh, Lavleen

    2013-01-01

    Ovarian stromal tumor with minor sex cord elements is a rare tumor. It is composed of predominantly fibrothecomatous tumor with scattered minor sex cord elements in less than 10% of the tumor area. These tumors may be hormonally active and predispose to carcinoma endometrium. A case of ovarian fibroma-thecoma with minor sex cord elements in which coexistent endometrial carcinoma was also discovered is being reported. Though thecoma may be a predisposing factor for endometrial cancer, meticulous histopathological examination of the ovary may reveal additional sources of estrogen like granulosa cell aggregates as in our patient. Such patients would require long-term follow-up to detect any recurrence of granulosa cell tumor.

  12. Mechanisms of tumor escape from immune system: role of mesenchymal stromal cells.

    PubMed

    Poggi, Alessandro; Musso, Alessandra; Dapino, Irene; Zocchi, Maria Raffaella

    2014-01-01

    Tumor microenvironment represents the site where the tumor tries to survive and escape from immune system-mediated recognition. Indeed, to proliferate tumor cells can divert the immune response inducing the generation of myeloid derived suppressor cells and regulatory T cells which can limit the efficiency of effector antitumor lymphocytes in eliminating neoplastic cells. Many components of the tumor microenvironment can serve as a double sword for the tumor and the host. Several types of fibroblast-like cells, which herein we define mesenchymal stromal cells (MSC), secrete extracellular matrix components and surrounding the tumor mass can limit the expansion of the tumor. On the other hand, MSC can interfere with the immune recognition of tumor cells producing immunoregulatory cytokines as transforming growth factor (TGF)ß, releasing soluble ligands of the activating receptors expressed on cytolytic effector cells as decoy molecules, affecting the correct interaction among lymphocytes and tumor cells. MSC can also serve as target for the same anti-tumor effector lymphocytes or simply impede the interaction between these lymphocytes and neoplastic cells. Thus, several evidences point out the role of MSC, both in epithelial solid tumors and hematological malignancies, in regulating tumor cell growth and immune response. Herein, we review these evidences and suggest that MSC can be a suitable target for a more efficient anti-tumor therapy.

  13. Endogenous and exogenous fluorescence of gastrointestinal tumors: initial clinical observations

    NASA Astrophysics Data System (ADS)

    Borisova, Ekaterina; Plamenova, Lilia; Keremedchiev, Momchil; Vladimirov, Borislav; Avramov, Latchezar

    2013-03-01

    The limitations of standard endoscopy for detection and evaluation of cancerous changes in gastrointestinal tract (GIT) are significant challenge and initiate development of new diagnostic modalities. Therefore many spectral and optical techniques are applied recently into the clinical practice for obtaining qualitatively and quantitatively new data from gastrointestinal neoplasia with different level of clinical applicability and diagnostic success. One of the most promising approaches is fluorescence detection using naturally existing fluorescent molecules or added fluorescent markers. Deltaaminolevulinic acid / protoporphyrin IX is applied for exogenous fluorescent tumor detection in the upper part of gastrointestinal tract. The 5-ALA is administered per os six hours before measurements at dose 20mg/kg weight. Highpower light-emitting diode at 405 nm is used as a source and the excitation light is passed through the light-guide of standard video-endoscopic system to obtain 2-D visualization. Both kinds of spectra - autofluorescence signals and protoporphyrin IX signal are recorded and stored using a fiber-optic microspectrometer, as in endoscopy instrumental channel a fiber is applied to return information about fluorescence signals. In such way 1-D detection and 2-D visualization of the lesions' fluorescence are received. The results from in vivo detection show significant differentiation between normal and abnormal tissues in 1-D spectroscopic regime, but only moderate discrimination in 2-D imaging.

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

    SciTech Connect

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

    2012-02-15

    Human mesenchymal stem cells (hMSCs) are bone marrow-derived stromal cells, which play a role in tumor progression. We have shown earlier that breast cancer cells secrete higher levels of interleukin-6 (IL-6) under hypoxia, leading to the recruitment of hMSCs towards hypoxic tumor cells. We found that (i) MDA-MB-231 cells secrete significantly higher levels of lactate (3-fold more) under hypoxia (1% O{sub 2}) than under 20% O{sub 2} and (ii) lactate recruits hMSCs towards tumor cells by activating signaling pathways to enhance migration. The mRNA and protein expression of functional MCT1 in hMSCs is increased in response to lactate exposure. Thus, we hypothesized that hMSCs and stromal carcinoma associated fibroblasts (CAFs) in the tumor microenvironment have the capacity to take up lactate expelled from tumor cells and use it as a source of energy. Our {sup 13}C NMR spectroscopic measurements indicate that {sup 13}C-lactate is converted to {sup 13}C-alpha ketoglutarate in hMSCs and CAFs supporting this hypothesis. To our knowledge this is the first in vitro model system demonstrating that hMSCs and CAFs can utilize lactate produced by tumor cells.

  15. Distinct effects of SIRT1 in cancer and stromal cells on tumor promotion.

    PubMed

    Shin, Dong Hoon; Choi, Yong-Joon; Jin, Peng; Yoon, Haejin; Chun, Yang-Sook; Shin, Hyun-Woo; Kim, Ja-Eun; Park, Jong-Wan

    2016-04-26

    The lysyl deacetylase SIRT1 acts as a metabolic sensor in adjusting metabolic imbalance. To explore the role of SIRT1 in tumor-stroma interplay, we designed an in vivo tumor model using SIRT1-transgenic mice. B16F10 mouse melanoma grew more quickly in SIRT1-transgenic mice than in wild-type mice, whereas SIRT1-overexpressing one grew slowly in both mice. Of human tumors, SIRT1 expression in stromal fibroblasts was found to correlate with poor prognosis in ovarian cancer. B16F10 and human ovarian cancer (SKOV3 and SNU840) cells were more proliferative in co-culture with SIRT1-overexpressiong fibroblasts. In contrast, SIRT1 within cancer cells has a negative effect on cell proliferation. In conditioned media from SIRT1-overexpressing fibroblasts, matrix metalloproteinase-3 (MMP3) was identified in cytokine arrays to be secreted from fibroblasts SIRT1-dependently. Fibroblast-derived MMP3 stimulated cancer cell proliferation, and such a role of MMP3 was also demonstrated in cancer/fibroblast co-grafts. In conclusion, SIRT1 plays differential roles in cancer and stromal cells. SIRT1 in stromal cells promotes cancer growth by producing MMP3, whereas SIRT1 in cancer cells inhibits growth via an intracellular event. The present study provides a basis for setting new anticancer strategies targeting SIRT1.

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

    PubMed Central

    Poggi, Alessandro; Giuliani, Massimo

    2016-01-01

    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. PMID:27834810

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

    PubMed

    Poggi, Alessandro; Giuliani, Massimo

    2016-11-08

    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.

  18. Mammary Tumor Development: Stromal-Epithelial Interactions in Oncogenesis.

    DTIC Science & Technology

    1996-09-01

    address experimentally the strong association of p53 mutations with human breast cancers, and to test whether this association holds for experimental...may develop secretory tumors (32,45,46). MG tumors are reported in transgenic mice expressing c-myc, c- erbB2 /neu, int-1, int-3 and Ha-ras, and in F1...Yasui, W, Takekura, N, Kameda, T, Oda, N, Ito, M, Ito, H, Tahara, E: Effect of epider- mal growth factor on rat stomach carcinogenesis induced by N

  19. Inhibition of tumor cells interacting with stromal cells by xanthones isolated from a Costa Rican Penicillium sp.

    PubMed

    Cao, Shugeng; McMillin, Douglas W; Tamayo, Giselle; Delmore, Jake; Mitsiades, Constantine S; Clardy, Jon

    2012-04-27

    CR1642D, an endophytic isolate of Penicillium sp. collected from a Costa Rican rainforest, was identified through a high-throughput approach to identify natural products with enhanced antitumor activity in the context of tumor-stromal interactions. Bioassay-guided separation led to the identification of five xanthones (1-5) from CR1642D. The structures of the xanthone dimer penexanthone A (1) and monomer penexanthone B (2) were elucidated on the basis of spectroscopic analyses, including 2D NMR experiments. All of the compounds were tested against a panel of tumor cell lines in the presence and absence of bone marrow stromal cells. Compound 3 was the most active, with IC(50) values of 1-17 μM, and its activity was enhanced 2-fold against tumor cell line RPMI8226 in the presence of stromal cells (IC(50) 1.2 μM, but 2.4 μM without stromal cells).

  20. A systematic review: perivascular epithelioid cell tumor of gastrointestinal tract

    PubMed Central

    Chen, Zehong; Han, Siqi; Wu, Jialin; Xiong, Minmin; Huang, Yanqiao; Chen, Jianhui; Yuan, Yujie; Peng, Jianjun; Song, Wu

    2016-01-01

    Abstract Perivascular epithelioid cell tumor (PEComa) is a rare entity with distinctive morphology and of expressing myomelanocytic markers. Gastrointestinal tract (GI) is one of the most common anatomic sites of origin and counts for 20% to 25% of all reported cases of perivascular epithelioid cell tumors not otherwise specified (PEComas-NOS). However, the biologic behavior of perivascular epithelioid cell tumors of gastrointestinal tract (GI PEComas-NOS) is still unclear. The aim of conducting this systematic review is to sum up what is known so far of the epidemiology, natural history, management and prognosis of GI PEComas-NOS. A systematic research was performed on PubMed and EMBASE using the following terms: (“perivascular epithelioid cell tumor” or “PEComa”) and (“gastrointestinal tract” or “GI” or “oral ” or “mouth” or “esophagus” or “gullet” or “gastric” or “stomach” or “duodenum” or “jejunum” or “ileum” or “cecum” or “colon” or “colorectal” or “sigmoid” or “rectum” or “anus” or “mesentery”) up to December 1, 2015. Retrieved GI PEComas-NOS publications, which included these terms, contains case reports, case series to case characteristic researches. A total of 168 articles were reviewed, 41 GI PEComa-NOS English studies among which were retrieved for analysis. We reviewed epidemiology, natural history, management and prognosis of GI PEComa-NOS. Generally GI PEComa-NOS is believed to have women predomination. The most frequently involved location is colon with non-specific clinical signs. Pathologically, GI PEComas-NOS shows epithelioid predominance (70%), meanwhile coexpresses melanocytic and muscle markers characteristically, while immunohistochemistry is a useful tool for identify, which indicates that HMB-45 is regarded as the most sensitive reagent. Complete resection served as mainstay of treatment, while chemotherapy should be unanimously considered to apply in malignant

  1. ADAMTS-1 metalloproteinase promotes tumor development through the induction of a stromal reaction in vivo.

    PubMed

    Rocks, Natacha; Paulissen, Geneviève; Quesada-Calvo, Florence; Munaut, Carine; Gonzalez, Maria-Luz Alvarez; Gueders, Maud; Hacha, Jonathan; Gilles, Christine; Foidart, Jean-Michel; Noel, Agnès; Cataldo, Didier D

    2008-11-15

    ADAMTS-1 (a disintegrin and metalloproteinase with thrombospondin motifs), the first described member of the ADAMTS family, is differentially expressed in various tumors. However, its exact role in tumor development and progression is still unclear. The aim of this study was to investigate the effects of ADAMTS-1 transfection in a bronchial epithelial tumor cell line (BZR) and its potential to modulate tumor development. ADAMTS-1 overexpression did not affect in vitro cell properties such as (a) proliferation in two-dimensional culture, (b) proliferation in three-dimensional culture, (c) anchorage-independent growth in soft agar, (d) cell migration and invasion in modified Boyden chamber assay, (e) angiogenesis in the aortic ring assay, and (f) cell apoptosis. In contrast, ADAMTS-1 stable transfection in BZR cells accelerated the in vivo tumor growth after s.c. injection into severe combined immunodeficient mice. It also promoted a stromal reaction characterized by myofibroblast infiltration and excessive matrix deposition. These features are, however, not observed in tumors derived from cells overexpressing a catalytically inactive mutant of ADAMTS-1. Conditioned media from ADAMTS-1-overexpressing cells display a potent chemotactic activity toward fibroblasts. ADAMTS-1 overexpression in tumors was associated with increased production of matrix metalloproteinase-13, fibronectin, transforming growth factor beta (TGF-beta), and interleukin-1beta (IL-1beta). Neutralizing antibodies against TGF-beta and IL-1beta blocked the chemotactic effect of medium conditioned by ADAMTS-1-expressing cells on fibroblasts, showing the contribution of these factors in ADAMTS-1-induced stromal reaction. In conclusion, we propose a new paradigm for catalytically active ADAMTS-1 contribution to tumor development, which consists of the recruitment of fibroblasts involved in tumor growth and tumor-associated stroma remodeling.

  2. The Roles of Mesenchymal Stromal/Stem Cells in Tumor Microenvironment Associated with Inflammation

    PubMed Central

    Krstić, Jelena; Djordjević, Ivana Okić; Jauković, Aleksandra

    2016-01-01

    State of tumor microenvironment (TME) is closely linked to regulation of tumor growth and progression affecting the final outcome, refractoriness, and relapse of disease. Interactions of tumor, immune, and mesenchymal stromal/stem cells (MSCs) have been recognized as crucial for understanding tumorigenesis. Due to their outstanding features, stem cell-like properties, capacity to regulate immune response, and dynamic functional phenotype dependent on microenvironmental stimuli, MSCs have been perceived as important players in TME. Signals provided by tumor-associated chronic inflammation educate MSCs to alter their phenotype and immunomodulatory potential in favor of tumor-biased state of MSCs. Adjustment of phenotype to TME and acquisition of tumor-promoting ability by MSCs help tumor cells in maintenance of permissive TME and suppression of antitumor immune response. Potential utilization of MSCs in treatment of tumor is based on their inherent ability to home tumor tissue that makes them suitable delivery vehicles for immune-stimulating factors and vectors for targeted antitumor therapy. Here, we review data regarding intrusive effects of inflammatory TME on MSCs capacity to affect tumor development through modification of their phenotype and interactions with immune system. PMID:27630452

  3. A mixed epithelial and stromal tumor of the kidney in a ringtail lemur (Lemur catta).

    PubMed

    Muller, S; Oevermann, A; Wenker, C; Altermatt, H J; Robert, N

    2007-03-01

    Primary renal tumors are rare neoplasms in nonhuman primates. This report describes a mixed epithelial and stromal tumor of the kidney (MESTK) in a 14.5-year-old female ringtail lemur. The well-demarcated, solid, and cystic mass was located in the pelvis of the left kidney and consisted histologically of both epithelial and mesenchymal components. The mesenchymal cells were arranged in fascicles around cysts lined by a well-differentiated epithelium. Neither the mesenchymal nor the epithelial parts showed significant nuclear atypia or mitotic figures. To our knowledge, only 1 similar case, classified as adenoleiomyofibromatous hamartoma, has been reported in a ringtail lemur. In humans this tumor affects predominantly perimenopausal women and can express estrogen and progesterone receptors. However, neither estrogen nor progesterone receptors could be identified by immunohistochemistry in the tumor of the present ringtail lemur. Therefore, a hormonal mechanism could not be demonstrated in this case.

  4. Regulators of Actin Dynamics in Gastrointestinal Tract Tumors

    PubMed Central

    Steinestel, Konrad; Wardelmann, Eva; Hartmann, Wolfgang; Grünewald, Inga

    2015-01-01

    Reorganization of the actin cytoskeleton underlies cell migration in a wide variety of physiological and pathological processes, such as embryonic development, wound healing, and tumor cell invasion. It has been shown that actin assembly and disassembly are precisely regulated by intracellular signaling cascades that respond to changes in the cell microenvironment, ligand binding to surface receptors, or oncogenic transformation of the cell. Actin-nucleating and actin-depolymerizing (ANFs/ADFs) and nucleation-promoting factors (NPFs) regulate cytoskeletal dynamics at the leading edge of migrating cells, thereby modulating cell shape; these proteins facilitate cellular movement and mediate degradation of the surrounding extracellular matrix by secretion of lytic proteases, thus eliminating barriers for tumor cell invasion. Accordingly, expression and activity of these actin-binding proteins have been linked to enhanced metastasis and poor prognosis in a variety of malignancies. In this review, we will summarize what is known about expression patterns and the functional role of actin regulators in gastrointestinal tumors and evaluate first pharmacological approaches to prevent invasion and metastatic dissemination of malignant cells. PMID:26345720

  5. Leptin as a mediator of tumor-stromal interactions promotes breast cancer stem cell activity.

    PubMed

    Giordano, Cinzia; Chemi, Francesca; Panza, Salvatore; Barone, Ines; Bonofiglio, Daniela; Lanzino, Marilena; Cordella, Angela; Campana, Antonella; Hashim, Adnan; Rizza, Pietro; Leggio, Antonella; Győrffy, Balázs; Simões, Bruno M; Clarke, Robert B; Weisz, Alessandro; Catalano, Stefania; Andò, Sebastiano

    2016-01-12

    Breast cancer stem cells (BCSCs) play crucial roles in tumor initiation, metastasis and therapeutic resistance. A strict dependency between BCSCs and stromal cell components of tumor microenvironment exists. Thus, novel therapeutic strategies aimed to target the crosstalk between activated microenvironment and BCSCs have the potential to improve clinical outcome. Here, we investigated how leptin, as a mediator of tumor-stromal interactions, may affect BCSC activity using patient-derived samples (n = 16) and breast cancer cell lines, and determined the potential benefit of targeting leptin signaling in these model systems. Conditioned media (CM) from cancer-associated fibroblasts and breast adipocytes significantly increased mammosphere formation in breast cancer cells and depletion of leptin from CM completely abrogated this effect. Mammosphere cultures exhibited increased leptin receptor (OBR) expression and leptin exposure enhanced mammosphere formation. Microarray analyses revealed a similar expression profile of genes involved in stem cell biology among mammospheres treated with CM and leptin. Interestingly, leptin increased mammosphere formation in metastatic breast cancers and expression of OBR as well as HSP90, a target of leptin signaling, were directly correlated with mammosphere formation in metastatic samples (r = 0.68/p = 0.05; r = 0.71/p = 0.036, respectively). Kaplan-Meier survival curves indicated that OBR and HSP90 expression were associated with reduced overall survival in breast cancer patients (HR = 1.9/p = 0.022; HR = 2.2/p = 0.00017, respectively). Furthermore, blocking leptin signaling by using a full leptin receptor antagonist significantly reduced mammosphere formation in breast cancer cell lines and patient-derived samples. Our results suggest that leptin/leptin receptor signaling may represent a potential therapeutic target that can block the stromal-tumor interactions driving BCSC-mediated disease progression.

  6. Multimodal treatment of gastrointestinal tract tumors: consequences for surgery.

    PubMed

    Siewert, J Rüdiger; Stein, Hubert J; von Rahden, Burkhard H A

    2005-08-01

    Formerly an exclusive business of surgery, gastrointestinal (GI) tumors are nowadays increasingly approached with multimodal strategies. Neoadjuvant concepts have had a particularly far-reaching impact on surgery and have contributed to improved survival. Modern pre-treatment staging and risk assessment provide the basis for decision on one of three general treatment concepts (1) Early cancers, confined to the mucosal/submucosal layers, are approached with primary surgery, without prior antineoplastic therapy. (2) Systemically metastasized tumors receive merely palliative treatment. (3) Locally advanced cancers are increasingly approached with neoadjuvant strategies. The benefit from these preoperative protocols is proven for diverse entities, but is evidently confined to a specific subgroup patients, i.e., the responders to neoadjuvant treatment. These are the ones benefiting most from subsequent surgical resection, which is required to ensure complete removal of the residual tumor tissue, as complete tumor regression occurs very rarely and cannot be proven without a specimen. The fact that responders will benefit and non-responders will not benefit or will even deteriorate during the neoadjuvant treatment makes early response prediction most demanding. An amazing new approach is the use of position emission tomography with fluro-desoxyglucose (FDG-PET) to assess the "metabolic response," which is possible as early as 14 days after initiation of the neoadjuvant protocol. This strategy offers the chance for modulating the surgical approach in accord i.e., with such metrobolic response termination of the protocol and proceeding to resection in the case of nonresponse. The future of GI cancer surgery is multimodal therapy in a response-based fashion and requires reponse-based trials for further evaluation.

  7. Virilizing Ovarian Stromal Tumor in a Young Woman With Carney Complex

    PubMed Central

    Carney, J. Aidan; Stratakis, Constantine A.

    2011-01-01

    A woman with Carney complex presented at age 22 years with abdominal pain and hirsutism. As a baby, she had excision of a right eyelid lesion and at age 14 years removal of a left lower eyelid nodule that subsequently recurred. Investigation revealed an elevated level of serum testosterone and a 2-cm left ovarian tumor. A left salpingo-oophorectomy was performed. Postoperatively, the abdominal pain was relieved, the serum level of testosterone was normalized, and the hirsutism was ameliorated. The tumor featured sheets of eosinophilic cells with lipochrome pigment, myeloid metaplasia, stromal metaplasia, and markedly abnormal blood vessels. Immunocytochemically, the tumor cells were positive for vimentin, synaptophysin, inhibin A and calrenin. Because of the clinical setting in which the neoplasm occurred, it is unlikely that the occurrence was unrelated to Carney complex.. PMID:21934476

  8. TGF-β in jaw tumor fluids induces RANKL expression in stromal fibroblasts

    PubMed Central

    Yamada, Chiaki; Aikawa, Tomonao; Okuno, Emi; Miyagawa, Kazuaki; Amano, Katsuhiko; Takahata, Sosuke; Kimata, Masaaki; Okura, Masaya; Iida, Seiji; Kogo, Mikihiko

    2016-01-01

    Odontogenic tumors and cysts, arising in the jawbones, grow by resorption and destruction of the jawbones. However, mechanisms underlying bone resorption by odontogenic tumors/cysts remain unclear. Odontogenic tumors/cysts comprise odontogenic epithelial cells and stromal fibroblasts, which originate from the developing tooth germ. It has been demonstrated that odontogenic epithelial cells of the developing tooth germ induce osteoclastogenesis to prevent the tooth germ from invading the developing bone to maintain its structure in developing bones. Thus, we hypothesized that odontogenic epithelial cells of odontogenic tumors/cysts induce osteoclast formation, which plays potential roles in tumor/cyst outgrowth into the jawbone. The purpose of this study was to examine osteoclastogenesis by cytokines, focusing on transforming growth factor-β (TGF-β), produced by odontogenic epithelial cells. We observed two pathways for receptor activator of NF-κB ligand (RANKL) induction by keratocystic odontogenic tumor fluid: the cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2) pathway through interleukin-1α (IL-1α) signaling and non-COX-2/PGE2 pathway through TGF-β receptor signaling. TGF-β1 and IL-1α produced by odontogenic tumors/cysts induced osteoclastogenesis directly in the osteoclast precursor cells and indirectly via increased RANKL induction in the stroma. PMID:27279422

  9. Toward Brain Tumor Gene Therapy Using Multipotent Mesenchymal Stromal Cell Vectors

    PubMed Central

    Bexell, Daniel; Scheding, Stefan; Bengzon, Johan

    2010-01-01

    Gene therapy of solid cancers has been severely restricted by the limited distribution of vectors within tumors. However, cellular vectors have emerged as an effective migratory system for gene delivery to invasive cancers. Implanted and injected multipotent mesenchymal stromal cells (MSCs) have shown tropism for several types of primary tumors and metastases. This capacity of MSCs forms the basis for their use as a gene vector system in neoplasms. Here, we review the tumor-directed migratory potential of MSCs, mechanisms of the migration, and the choice of therapeutic transgenes, with a focus on malignant gliomas as a model system for invasive and highly vascularized tumors. We examine recent findings demonstrating that MSCs share many characteristics with pericytes and that implanted MSCs localize primarily to perivascular niches within tumors, which might have therapeutic implications. The use of MSC vectors in cancer gene therapy raises concerns, however, including a possible MSC contribution to tumor stroma and vasculature, MSC-mediated antitumor immune suppression, and the potential malignant transformation of cultured MSCs. Nonetheless, we highlight the novel prospects of MSC-based tumor therapy, which appears to be a promising approach. PMID:20407426

  10. Can contrast-enhanced harmonic endosonography predict malignancy risk in gastrointestinal subepithelial tumors?

    PubMed Central

    Park, Hye Yoon; Jeon, Seong Woo; Lee, Hyun Seok; Cho, Chang Min; Bae, Han Ik; Seo, An Na; Kweon, Oh Kyung

    2016-01-01

    Background and Objectives: Contrast-enhanced harmonic endoscopic ultrasound (CEH-EUS) is a novel technology that can identify subepithelial tumors (SETs) by detecting the degree of enhancement, but whether CEH-EUS can predict the malignancy risk of gastrointestinal stromal tumors (GISTs) remains unclear. The aim of our study was to evaluate the diagnostic accuracy of CEH-EUS and its ability to discriminate among SETs and predict the malignancy risk of GISTs. Materials and Methods: We retrospectively included patients with suspected subepithelial lesions who underwent CEH-EUS preoperatively. Thirty-five patients with histologically proven GISTs and benign neoplasms were enrolled in the study. The images of CEH-EUS were categorized in accordance with microvasculature, parenchymal perfusion, and nonenhancing spots. The diagnostic performance of CEH-EUS was evaluated by comparing these findings with the histological diagnosis. Results: When we divided the enrolled patients into high- and low-grade malignancy and benign groups, nonenhancing spots on CEH-EUS were found more frequently in the high-grade malignancy group (63.6%), followed by the low-grade malignancy (46.7%) and benign groups (25.7%) (P = 0.022). However, based on the statistical validity of the CEH-EUS findings for the discrimination of SETs, the sensitivity was 53.8% for diagnostic performance and 63.6% for prediction of malignancy risk of GISTs. Conclusions: From our study results, it is unclear whether CEH-EUS alone has a diagnostic role in the discrimination of SETs and the prediction of malignancy risk of GISTs. Further studies with larger samples from multiple centers and use of other imaging analysis modalities are needed. PMID:28000630

  11. Pyruvate kinase expression (PKM1 and PKM2) in cancer-associated fibroblasts drives stromal nutrient production and tumor growth.

    PubMed

    Chiavarina, Barbara; Whitaker-Menezes, Diana; Martinez-Outschoorn, Ubaldo E; Witkiewicz, Agnieszka K; Birbe, Ruth; Howell, Anthony; Pestell, Richard G; Smith, Johanna; Daniel, Rene; Sotgia, Federica; Lisanti, Michael P

    2011-12-15

    We have previously demonstrated that enhanced aerobic glycolysis and/or autophagy in the tumor stroma supports epithelial cancer cell growth and aggressive behavior, via the secretion of high-energy metabolites. These nutrients include lactate and ketones, as well as chemical building blocks, such as amino acids (glutamine) and nucleotides. Lactate and ketones serve as fuel for cancer cell oxidative metabolism, and building blocks sustain the anabolic needs of rapidly proliferating cancer cells. We have termed these novel concepts the "Reverse Warburg Effect," and the "Autophagic Tumor Stroma Model of Cancer Metabolism." We have also identified a loss of stromal caveolin-1 (Cav-1) as a marker of stromal glycolysis and autophagy. The aim of the current study was to provide genetic evidence that enhanced glycolysis in stromal cells favors tumorigenesis. To this end, normal human fibroblasts were genetically-engineered to express the two isoforms of pyruvate kinase M (PKM1 and PKM2), a key enzyme in the glycolytic pathway. In a xenograft model, fibroblasts expressing PKM1 or PKM2 greatly promoted the growth of co-injected MDA-MB-231 breast cancer cells, without an increase in tumor angiogenesis. Interestingly, PKM1 and PKM2 promoted tumorigenesis by different mechanism(s). Expression of PKM1 enhanced the glycolytic power of stromal cells, with increased output of lactate. Analysis of tumor xenografts demonstrated that PKM1 fibroblasts greatly induced tumor inflammation, as judged by CD45 staining. In contrast, PKM2 did not lead to lactate accumulation, but triggered a "pseudo-starvation" response in stromal cells, with induction of an NFκB-dependent autophagic program, and increased output of the ketone body 3-hydroxy-buryrate. Strikingly, in situ evaluation of Complex IV activity in the tumor xenografts demonstrated that stromal PKM2 expression drives mitochondrial respiration specifically in tumor cells. Finally, immuno-histochemistry analysis of human breast

  12. High-risk gastrointestinal stromal tumour (GIST) and synovial sarcoma display similar angiogenic profiles: a nude mice xenograft study

    PubMed Central

    Giner, Francisco; Machado, Isidro; Lopez-Guerrero, Jose Antonio; Mayordomo-Aranda, Empar; Llombart-Bosch, Antonio

    2017-01-01

    Background Gastrointestinal stromal tumour (GIST) is the most common primary mesenchymal tumour of the gastrointestinal tract. Spindle cell monophasic synovial sarcoma (SS) can be morphologically similar. Angiogenesis is a major factor for tumour growth and metastasis. Our aim was to compare the angiogenic expression profiles of high-risk GIST and spindle cell monophasic SS by histological, immunohistochemical and molecular characterisation of the neovascularisation established between xenotransplanted tumours and the host during the initial phases of growth in nude mice. Methods The angiogenic profile of two xenotransplanted human soft-tissue tumours were evaluated in 15 passages in nude mice using tissue microarrays (TMA). Tumour pieces were also implanted subcutaneously on the backs of 14 athymic Balb-c nude mice. The animals were sacrificed at 24, 48, and 96 h; and 7, 14, 21, and 28 days after implantation to perform histological, immunohistochemical, and molecular studies (neovascularisation experiments). Results Morphological similarities were apparent in the early stages of neoplastic growth of these two soft-tissue tumours throughout the passages in nude mice and in the two neovascularisation experiments. Immunohistochemistry demonstrated overexpression of pro-angiogenic factors between 24 h and 96 h after xenotransplantation in both tumours. Additionally, neoplastic cells coexpressed chemokines (CXCL9, CXCL10, GRO, and CXCL12) and their receptors in both tumours. Molecular studies showed two expression profiles, revealing an early and a late phase in the angiogenic process. Conclusion This model could provide information on the early stages of the angiogenic process in monophasic spindle cell SS and high-risk GIST and offers an excellent way to study possible tumour response to antiangiogenic drugs. PMID:28386296

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

    SciTech Connect

    Schick, Ulrike; Bolukbasi, Yasmin; Thariat, Juliette; Abdah-Bortnyak, Roxolyana; Kuten, Abraham; Igdem, Sefik; Caglar, Hale; Ozsaran, Zeynep; Loessl, Kristina; Schleicher, Ursula; Zwahlen, Daniel; Villette, Sylviane; Vees, Hansjoerg

    2012-04-01

    Purpose: To provide further understanding regarding outcome and prognostic factors of endometrial stromal tumors (EST). Methods and Materials: A retrospective analysis was performed on the records of 59 women diagnosed with EST and treated with curative intent between 1983 and 2007 in the framework of the Rare Cancer Network. Results: Endometrial stromal sarcomas (ESS) were found in 44% and undifferentiated ESS (UES) in 49% of the cases. In 7% the grading was unclear. Of the total number of patients, 33 had Stage I, 4 Stage II, 20 Stage III, and 1 presented with Stage IVB disease. Adjuvant chemotherapy was administered to 12 patients, all with UES. External-beam radiotherapy (RT) was administered postoperatively to 48 women. The median follow-up was 41.4 months. The 5-year overall survival (OS) rate was 96.2% and 64.8% for ESS and UES, respectively, with a corresponding 5-year disease-free survival (DFS) rate of 49.4% and 43.4%, respectively. On multivariate analysis, adjuvant RT was an independent prognostic factor for OS (p = 0.007) and DFS (p = 0.013). Locoregional control, DFS, and OS were significantly associated with age ({<=}60 vs. >60 years), grade (ESS vs. UES), and International Federation of Gynecology and Obstetrics stage (I-II vs. III-IV). Positive lymph node staging had an impact on OS (p < 0.001). Conclusion: The prognosis of ESS differed from that of UES. Endometrial stromal sarcomas had an excellent 5-year OS, whereas the OS in UES was rather low. However, half of ESS patients had a relapse. For this reason, adjuvant treatment such as RT should be considered even in low-grade tumors. Multicenter randomized studies are still warranted to establish clear guidelines.

  14. Cystic nephroma/mixed epithelial stromal tumor: a benign neoplasm with potential for recurrence.

    PubMed

    Sun, Belinda L; Abern, Michael; Garzon, Steven; Setty, Suman

    2015-05-01

    Cystic nephroma (CN) is a rare, benign, renal neoplasm composed of epithelial and stromal elements. Only about 200 cases have been reported since 1892 and recurrence has rarely been observed. We report a 32-year-old Hispanic woman, with a history of a right, complex cystic, renal mass treated by robotic decortication 2 years ago, who presented with flank pain, hematuria, and recurrent urinary tract infection. A magnetic resonance imaging study showed a 3.4-cm multicystic lesion with thickened septa and enhancement at the right kidney. The partial nephrectomy specimen revealed a well-circumscribed, multicystic tumor abutting the renal pelvis, with thick septa and smooth walls, filled with clear fluid. Microscopic examination showed variably sized cysts lined by cuboidal epithelium with focal hobnailing, without significant cytologic atypia and mitosis. The epithelial lining was positive for CK19, high molecular weight cytokeratin, and α-methylacyl-CoA racemase suggesting a primitive tubular epithelial phenotype. Primitive glomeruli-like structures were also present. The ovarian-like stroma was condensed around the cysts and was variably cellular with areas of muscle differentiation and thick-walled vessels. The stroma was positive for desmin, estrogen receptor, progesterone receptor, and CD10. We suggest that CN represents a variable mixture of epithelial and stromal elements, immature glomerular, tubular, muscle, and vascular elements, which may be present in variable proportions creating a spectrum of lesions previously described as CN and mixed epithelial and stromal tumors (MEST). This case emphasizes that CN/MEST clinically/radiologically mimics other cystic renal neoplasms, especially cystic renal cell carcinoma and tubulocystic carcinoma, necessitating histopathological examination and immunohistochemial studies for definitive diagnosis. Additionally, CN has the tendency to recur when not completely excised initially.

  15. Elevated Epidermal Thymic Stromal Lymphopoietin Levels Establish an Anti-Tumor Environment in the Skin

    PubMed Central

    Demehri, Shadmehr; Turkoz, Ahu; Manivasagam, Sindhu; Yockey, Laura J.; Turkoz, Mustafa; Kopan, Raphael

    2012-01-01

    Summary Thymic Stromal Lymphopoietin (TSLP), a cytokine implicated in induction of T helper 2 (Th2)-mediated allergic inflammation, has recently been shown to stimulate solid tumor growth and metastasis. Conversely, studying mice with clonal loss of Notch signaling in their skin revealed that high levels of TSLP released by barrier-defective skin caused a severe inflammation, resulting in gradual elimination of Notch-deficient epidermal clones and resistance to skin tumorigenesis. We found CD4+ T cells to be both required and sufficient to mediate these effects of TSLP. Importantly, TSLP overexpression in wild-type skin also caused resistance to tumorigenesis, confirming that TSLP functions as a tumor suppressor in the skin. PMID:23079659

  16. Sporadic diffuse segmental interstitial cell of Cajal hyperplasia harbouring two gastric gastrointestinal stromal tumours (GIST) mimicking hereditary GIST syndromes

    PubMed Central

    Neves, Mafalda Costa; Stamp, Gordon; Mudan, Satvinder

    2015-01-01

    Introduction Gastrointestinal stromal tumours (GISTs) are thought to derive from or differentiate towards the interstitial cells of Cajal (ICC) as most demonstrate a similar immunoprofile: CD117+, CD34+ and DOG1+. ICC hyperplasia refers to KIT-expressing microscopic spindle cell proliferations involving the myenteric plexus. Case report 74 year-old male presented with a 5-year history of heartburn and dysphagia. Imaging revealed a 4 cm GIST in the gastric fundus. Pathology of the resected specimen revealed diffuse segmental ICC hyperplasia harbouring two macroscopic GISTs and a ‘tumorlet’. A mutation in c-KIT exon 11 was detected in both the solid and the diffuse components. Discussion ICC hyperplasia can occur either as a sporadic focal lesion or in a syndromic setting, known to predispose to multiple GIST tumours at different sites. The majority of cases of sporadic ICC hyperplasia previously reported were of localised type. The hereditary form is mostly caused by germline mutations in c-KIT and PDGFRA or in patients with NF-1 andpresents as a diffuse hyperplasia, usually with a confluent, nodular or multifocal growth pattern. Conclusion We describe a diffuse form of sporadic ICC hyperplasia harbouring multifocal GISTs, mimicking diffuse ICC hyperplasia in hereditary GIST syndromes. Detection of somatic c-KIT exon 11 mutation ruled out a hereditary disorder. PMID:26521201

  17. Exosomes from human colorectal cancer induce a tumor-like behavior in colonic mesenchymal stromal cells

    PubMed Central

    Lugini, Luana; Valtieri, Mauro; Federici, Cristina; Cecchetti, Serena; Meschini, Stefania; Condello, Maria; Signore, Michele; Fais, Stefano

    2016-01-01

    Background Cancer cells, including colorectal cancer ones (CRC), release high amounts of nanovesicles (exosomes), delivering biochemical messages for paracrine or systemic crosstalk. Mesenchymal stromal cells (MSCs) have been shown to play contradicting roles in tumor progression. Results CRC exosomes induce in cMSCs: i) atypical morphology, higher proliferation, migration and invasion; ii) formation of spheroids; iii) an acidic extracellular environment associated with iv) a plasma membrane redistribution of vacuolar H+-ATPase and increased expression of CEA. Colon cancer derived MSCs, which were isolated from tumor masses, produce umbilicated spheroids, a future frequently observed in the inner core of rapidly growing tumors and recapitulate the changes observed in normal colonic MSCs exposed to CRC exosomes. Materials and Methods Tissue specific colonic (c)MSCs were exposed to primary or metastatic CRC exosomes and analysed by light and electron microscopy, proliferation in 2D and 3D cultures, migration and invasion assays, Western blot and confocal microscopy for vacuolar H+-ATPase expression. Conclusions CRC exosomes are able to induce morphological and functional changes in colonic MSCs, which may favour tumor growth and its malignant progression. Our results suggest that exosomes are actively involved in cancer progression and that inhibiting tumor exosome release may represent a way to interfere with cancer. PMID:27418137

  18. Tumor-associated macrophages and stromal TNF-α regulate collagen structure in a breast tumor model as visualized by second harmonic generation.

    PubMed

    Burke, Ryan M; Madden, Kelley S; Perry, Seth W; Zettel, Martha L; Brown, Edward B

    2013-08-01

    Collagen fibers can be imaged with second harmonic generation (SHG) and are associated with efficient tumor cell locomotion. Preferential locomotion along these fibers correlates with a more aggressively metastatic phenotype, and changes in SHG emission properties accompany changes in metastatic outcome. We therefore attempted to elucidate the cellular and molecular machinery that influences SHG in order to understand how the microstructure of tumor collagen fibers is regulated. By quantifying SHG and immunofluorescence (IF) from tumors grown in mice with and without stromal tumor necrosis factor (TNF)-α and in the presence or absence of tumor-associated macrophages (TAMs), we determined that depletion of TAMs alters tumor collagen fibrillar microstructure as quantified by SHG and IF. Furthermore, we determined that abrogation of TNF-α expression by tumor stromal cells also alters fibrillar microstructure and that subsequent depletion of TAMs has no further effect. In each case, metastatic burden correlated with optical readouts of collagen microstructure. Our results implicate TAMs and stromal TNF-α as regulators of breast tumor collagen microstructure and suggest that this regulation plays a role in tumor metastasis. Furthermore, these results indicate that quantification of SHG represents a useful strategy for evaluating the cells and molecular pathways responsible for manipulating fibrillar collagen in breast tumor models.

  19. Tumor-associated macrophages and stromal TNF-α regulate collagen structure in a breast tumor model as visualized by second harmonic generation

    NASA Astrophysics Data System (ADS)

    Burke, Ryan M.; Madden, Kelley S.; Perry, Seth W.; Zettel, Martha L.; Brown, Edward B.

    2013-08-01

    Collagen fibers can be imaged with second harmonic generation (SHG) and are associated with efficient tumor cell locomotion. Preferential locomotion along these fibers correlates with a more aggressively metastatic phenotype, and changes in SHG emission properties accompany changes in metastatic outcome. We therefore attempted to elucidate the cellular and molecular machinery that influences SHG in order to understand how the microstructure of tumor collagen fibers is regulated. By quantifying SHG and immunofluorescence (IF) from tumors grown in mice with and without stromal tumor necrosis factor (TNF)-α and in the presence or absence of tumor-associated macrophages (TAMs), we determined that depletion of TAMs alters tumor collagen fibrillar microstructure as quantified by SHG and IF. Furthermore, we determined that abrogation of TNF-α expression by tumor stromal cells also alters fibrillar microstructure and that subsequent depletion of TAMs has no further effect. In each case, metastatic burden correlated with optical readouts of collagen microstructure. Our results implicate TAMs and stromal TNF-α as regulators of breast tumor collagen microstructure and suggest that this regulation plays a role in tumor metastasis. Furthermore, these results indicate that quantification of SHG represents a useful strategy for evaluating the cells and molecular pathways responsible for manipulating fibrillar collagen in breast tumor models.

  20. Whole transcriptome profiling of patient-derived xenograft models as a tool to identify both tumor and stromal specific biomarkers

    PubMed Central

    Bradford, James R.; Wappett, Mark; Beran, Garry; Logie, Armelle; Delpuech, Oona; Brown, Henry; Boros, Joanna; Camp, Nicola J.; McEwen, Robert; Mazzola, Anne Marie; D'Cruz, Celina; Barry, Simon T.

    2016-01-01

    The tumor microenvironment is emerging as a key regulator of cancer growth and progression, however the exact mechanisms of interaction with the tumor are poorly understood. Whilst the majority of genomic profiling efforts thus far have focused on the tumor, here we investigate RNA-Seq as a hypothesis-free tool to generate independent tumor and stromal biomarkers, and explore tumor-stroma interactions by exploiting the human-murine compartment specificity of patient-derived xenografts (PDX). Across a pan-cancer cohort of 79 PDX models, we determine that mouse stroma can be separated into distinct clusters, each corresponding to a specific stromal cell type. This implies heterogeneous recruitment of mouse stroma to the xenograft independent of tumor type. We then generate cross-species expression networks to recapitulate a known association between tumor epithelial cells and fibroblast activation, and propose a potentially novel relationship between two hypoxia-associated genes, human MIF and mouse Ddx6. Assessment of disease subtype also reveals MMP12 as a putative stromal marker of triple-negative breast cancer. Finally, we establish that our ability to dissect recruited stroma from trans-differentiated tumor cells is crucial to identifying stem-like poor-prognosis signatures in the tumor compartment. In conclusion, RNA-Seq is a powerful, cost-effective solution to global analysis of human tumor and mouse stroma simultaneously, providing new insights into mouse stromal heterogeneity and compartment-specific disease markers that are otherwise overlooked by alternative technologies. The study represents the first comprehensive analysis of its kind across multiple PDX models, and supports adoption of the approach in pre-clinical drug efficacy studies, and compartment-specific biomarker discovery. PMID:26980748

  1. Whole transcriptome profiling of patient-derived xenograft models as a tool to identify both tumor and stromal specific biomarkers.

    PubMed

    Bradford, James R; Wappett, Mark; Beran, Garry; Logie, Armelle; Delpuech, Oona; Brown, Henry; Boros, Joanna; Camp, Nicola J; McEwen, Robert; Mazzola, Anne Marie; D'Cruz, Celina; Barry, Simon T

    2016-04-12

    The tumor microenvironment is emerging as a key regulator of cancer growth and progression, however the exact mechanisms of interaction with the tumor are poorly understood. Whilst the majority of genomic profiling efforts thus far have focused on the tumor, here we investigate RNA-Seq as a hypothesis-free tool to generate independent tumor and stromal biomarkers, and explore tumor-stroma interactions by exploiting the human-murine compartment specificity of patient-derived xenografts (PDX).Across a pan-cancer cohort of 79 PDX models, we determine that mouse stroma can be separated into distinct clusters, each corresponding to a specific stromal cell type. This implies heterogeneous recruitment of mouse stroma to the xenograft independent of tumor type. We then generate cross-species expression networks to recapitulate a known association between tumor epithelial cells and fibroblast activation, and propose a potentially novel relationship between two hypoxia-associated genes, human MIF and mouse Ddx6. Assessment of disease subtype also reveals MMP12 as a putative stromal marker of triple-negative breast cancer. Finally, we establish that our ability to dissect recruited stroma from trans-differentiated tumor cells is crucial to identifying stem-like poor-prognosis signatures in the tumor compartment.In conclusion, RNA-Seq is a powerful, cost-effective solution to global analysis of human tumor and mouse stroma simultaneously, providing new insights into mouse stromal heterogeneity and compartment-specific disease markers that are otherwise overlooked by alternative technologies. The study represents the first comprehensive analysis of its kind across multiple PDX models, and supports adoption of the approach in pre-clinical drug efficacy studies, and compartment-specific biomarker discovery.

  2. The Action of Discoidin Domain Receptor 2 in Basal Tumor Cells and Stromal Cancer-Associated Fibroblasts Is Critical for Breast Cancer Metastasis.

    PubMed

    Corsa, Callie A S; Brenot, Audrey; Grither, Whitney R; Van Hove, Samantha; Loza, Andrew J; Zhang, Kun; Ponik, Suzanne M; Liu, Yuming; DeNardo, David G; Eliceiri, Kevin W; Keely, Patricia J; Longmore, Gregory D

    2016-06-14

    High levels of collagen deposition in human and mouse breast tumors are associated with poor outcome due to increased local invasion and distant metastases. Using a genetic approach, we show that, in mice, the action of the fibrillar collagen receptor discoidin domain receptor 2 (DDR2) in both tumor and tumor-stromal cells is critical for breast cancer metastasis yet does not affect primary tumor growth. In tumor cells, DDR2 in basal epithelial cells regulates the collective invasion of tumor organoids. In stromal cancer-associated fibroblasts (CAFs), DDR2 is critical for extracellular matrix production and the organization of collagen fibers. The action of DDR2 in CAFs also enhances tumor cell collective invasion through a pathway distinct from the tumor-cell-intrinsic function of DDR2. This work identifies DDR2 as a potential therapeutic target that controls breast cancer metastases through its action in both tumor cells and tumor-stromal cells at the primary tumor site.

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

    PubMed

    Fröhlich, Camilla; Nehammer, Camilla; Albrechtsen, Reidar; Kronqvist, Pauliina; Kveiborg, Marie; Sehara-Fujisawa, Atsuko; Mercurio, Arthur M; Wewer, Ulla M

    2011-11-01

    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 this study, we found that ADAM12 deficiency reduces breast tumor progression in the PyMT model. However, the catalytic activity of ADAM12 seems to be dispensable for its tumor-promoting effect. Interestingly, we show 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 hypothesized, however, that the tumor-associated stroma may stimulate ADAM12 expression in tumor cells, on the basis of the fact that TGF-β1 stimulates ADAM12 expression and is a well-known growth factor released from tumor-associated stroma. TGF-β1 stimulation of ADAM12-negative Lewis lung tumor cells induced ADAM12 synthesis, and growth of these cells in vivo induced more than 200-fold increase in ADAM12 expression. Our observation that ADAM12 expression is significantly higher in the terminal duct lobular units (TDLU) adjacent to human breast carcinoma compared with TDLUs found in normal breast tissue supports our hypothesis that tumor-associated stroma triggers ADAM12 expression.

  4. Inhibition of Tumor Cells Interacting with Stromal Cells by Xanthones Isolated from a Costa Rican Penicillium sp.

    PubMed Central

    Cao, Shugeng; McMillin, Douglas W.; Tamayo, Giselle; Delmore, Jake; Mitsiades, Constantine S.; Clardy, Jon

    2012-01-01

    CR1642D, an endophytic isolate of Penicillium sp. collected from a Costa Rican rainforest, was identified through a high-throughput approach to identify natural products with enhanced anti-tumor activity in the context of tumor-stromal interactions. Bioassay-guided separation led to the identification of five xanthones (1-5) from CR1642D. The structures of the xanthone dimer penexanthone A (1) and monomer penexanthone B (2) were elucidated on the basis of spectroscopic analyses, including 2D NMR experiments. All of the compounds were tested against a panel of tumor cell lines in the presence and absence of bone marrow stromal cells. Compound 3 was the most active, with IC50 values of 1~17 μM, and its activity was enhanced two-fold against tumor cell line RPMI8226 in the presence of stromal cells (IC50 1.2 μM, but 2.4 μM without stromal cells). PMID:22458669

  5. Comparative proteomic analysis of normal and tumor stromal cells by tissue on chip based mass spectrometry (toc-MS)

    PubMed Central

    2010-01-01

    In carcinoma tissues, genetic and metabolic changes not only occur at the tumor cell level, but also in the surrounding stroma. This carcinoma-reactive stromal tissue is heterogeneous and consists e.g. of non-epithelial cells such as fibroblasts or fibrocytes, inflammatory cells and vasculature-related cells, which promote carcinoma growth and progression of carcinomas. Nevertheless, there is just little knowledge about the proteomic changes from normal connective tissue to tumor stroma. In the present study, we acquired and analysed specific protein patterns of small stromal sections surrounding head and neck cell complexes in comparison to normal subepithelial connective tissue. To gain defined stromal areas we used laser-based tissue microdissection. Because these stromal areas are limited in size we established the highly sensitive 'tissue on chip based mass spectrometry' (toc-MS). Therefore, the dissected areas were directly transferred to chromatographic arrays and the proteomic profiles were subsequently analysed with mass spectrometry. At least 100 cells were needed for an adequate spectrum. The locating of differentially expressed proteins enables a precise separation of normal and tumor stroma. The newly described toc-MS technology allows an initial insight into proteomic differences between small numbers of exactly defined cells from normal and tumor stroma. PMID:20205871

  6. Stromal Barriers and Strategies for the Delivery of Nanomedicine to Desmoplastic Tumors

    PubMed Central

    Miao, Lei; Lin, C. Michael; Huang, Leaf

    2015-01-01

    Nanoparticle based delivery formulations have become a leading delivery strategy for cancer imaging and therapy. The success of nanoparticle-based therapy relies heavily on their ability to utilize the enhanced permeability and retention (EPR) effect and active targeting moieties to their advantage. However, these methods often fail to enable a uniform NP distribution across the tumor, and lead to insufficient local concentrations of drug. Oftentimes, this heterogeneous drug distribution is one of the primary reasons for suboptimal treatment efficacy in NP delivery platforms. Herein, we seek to examine the biophysical causes of heterogeneous NP distribution in stroma-rich desmoplastic tumors; namely the abnormal tumor vasculature, deregulated extracellular matrix and high interstitial hypertension associated with these tumors. It is suggested that these factors help explain the discrepancy between promising outlooks for many NP formulations in preclinical studies, but suboptimal clinical outcomes for most FDA approved nanoformulations. Furthermore, examination into the role of the physicochemical properties of NPs on successful drug delivery was conducted in this review. In light of the many formidable barriers against successful NP drug delivery, we provided possible approaches to mitigate delivery issues from the perspective of stromal remodeling and NP design. In all, this review seeks to provide guidelines for optimizing nanoparticle-based cancer drug delivery through both modified nanoparticle design and alleviation of biological barriers to successful therapy. PMID:26277065

  7. Inorganic Arsenic–Related Changes in the Stromal Tumor Microenvironment in a Prostate Cancer Cell–Conditioned Media Model

    PubMed Central

    Shearer, Joseph J.; Wold, Eric A.; Umbaugh, Charles S.; Lichti, Cheryl F.; Nilsson, Carol L.; Figueiredo, Marxa L.

    2015-01-01

    Background: The tumor microenvironment plays an important role in the progression of cancer by mediating stromal–epithelial paracrine signaling, which can aberrantly modulate cellular proliferation and tumorigenesis. Exposure to environmental toxicants, such as inorganic arsenic (iAs), has also been implicated in the progression of prostate cancer. Objective: The role of iAs exposure in stromal signaling in the tumor microenvironment has been largely unexplored. Our objective was to elucidate molecular mechanisms of iAs-induced changes to stromal signaling by an enriched prostate tumor microenvironment cell population, adipose-derived mesenchymal stem/stromal cells (ASCs). Results: ASC-conditioned media (CM) collected after 1 week of iAs exposure increased prostate cancer cell viability, whereas CM from ASCs that received no iAs exposure decreased cell viability. Cytokine array analysis suggested changes to cytokine signaling associated with iAs exposure. Subsequent proteomic analysis suggested a concentration-dependent alteration to the HMOX1/THBS1/TGFβ signaling pathway by iAs. These results were validated by quantitative reverse transcriptase–polymerase chain reaction (RT-PCR) and Western blotting, confirming a concentration-dependent increase in HMOX1 and a decrease in THBS1 expression in ASC following iAs exposure. Subsequently, we used a TGFβ pathway reporter construct to confirm a decrease in stromal TGFβ signaling in ASC following iAs exposure. Conclusions: Our results suggest a concentration-dependent alteration of stromal signaling: specifically, attenuation of stromal-mediated TGFβ signaling following exposure to iAs. Our results indicate iAs may enhance prostate cancer cell viability through a previously unreported stromal-based mechanism. These findings indicate that the stroma may mediate the effects of iAs in tumor progression, which may have future therapeutic implications. Citation: Shearer JJ, Wold EA, Umbaugh CS, Lichti CF, Nilsson CL

  8. Folate-related polymorphisms in gastrointestinal stromal tumours: susceptibility and correlation with tumour characteristics and clinical outcome

    PubMed Central

    Angelini, Sabrina; Ravegnini, Gloria; Nannini, Margherita; Bermejo, Justo Lorenzo; Musti, Muriel; Pantaleo, Maria A; Fumagalli, Elena; Venturoli, Nicola; Palassini, Elena; Consolini, Nicola; Casali, Paolo G; Biasco, Guido; Hrelia, Patrizia

    2015-01-01

    The folate metabolism pathway has a crucial role in tumorigenesis as it supports numerous critical intracellular reactions, including DNA synthesis, repair, and methylation. Despite its importance, little is known about the influence of the folate pathway on gastrointestinal stromal tumour (GIST), a rare tumour with an incidence ranging between 6 and 19.6 cases per million worldwide. The importance of folate metabolism led us to investigate the influence of polymorphisms in the genes coding folate-metabolising enzymes on GIST susceptibility, tumour characteristics and clinical outcome. We investigated a panel of 13 polymorphisms in 8 genes in 60 cases and 153 controls. The TS 6-bp deletion allele (formerly rs34489327, delTInsTTAAAG) was associated with reduced risk of GIST (OR=0.20, 95% CI 0.05–0.67, P=0.0032). Selected polymorphisms in patients stratified by age, gender, and other main molecular and clinical characteristics showed that few genotypes may show a likely correlation. We also observed a significant association between the RFC AA/AG genotype and time to progression (HR=0.107, 95% CI 0.014–0.82; P=0.032). Furthermore, we observed a tendency towards an association between the SHMT1 variant allele (TT, rs1979277) and early death (HR=4.53, 95% CI 0.77–26.58, P=0.087). Aware of the strengths and limitations of the study, these results suggest that polymorphisms may modify the risk of GIST and clinical outcome, pointing to the necessity for further investigations with information on folate plasma levels and a larger study population. PMID:25227144

  9. Comparison of the anti-tumor effects of denosumab and zoledronic acid on the neoplastic stromal cells of giant cell tumor of bone.

    PubMed

    Lau, Carol P Y; Huang, Lin; Wong, Kwok Chuen; Kumta, Shekhar Madhukar

    2013-01-01

    Denosumab and Zoledronic acid (ZOL) are two antiresorptive drugs currently in use for treating osteoporosis. They have different mechanisms of action but both have been shown to delay the onset of skeletal-related events in patients with giant cell tumor of bone (GCT). However, the anti-tumor mechanisms of denosumab on the neoplastic GCT stromal cells remain unknown. In this study, we focused on the direct effects of denosumab on the neoplastic GCT stromal cells and compared with ZOL. The microscopic view demonstrated a reduced cell growth in ZOL-treated but not in denosumab-treated GCT stromal cells. ZOL was found to exhibit a dose-dependent inhibition in cell growth in all GCT stromal cell lines tested and cause apoptosis in two out of three cell lines. In contrast, denosumab only exerted a minimal inhibitory effect in one cell line and did not induce any apoptosis. ZOL significantly inhibited the mRNA expression of receptor activator of nuclear factor kappa-B ligand (RANKL) and osteoprotegerin (OPG) in two GCT stromal cell lines whereas their protein levels remained unchanged. On the contrary, denosumab did not regulate RANKL and OPG expression at both mRNA and protein levels. Moreover, the protein expression of Macrophage Colony-Stimulating Factor (M-CSF), Alkaline Phosphatase (ALP), and Collagen α1 Type I were not regulated by denosumab and ZOL either. Our findings provide new insights in the anti-tumor effect of denosumab on GCT stromal cells and raise a concern that tumor recurrence may occur after the withdrawal of the drug.

  10. Ovarian mucinous epithelial neoplasm showing immunohistochemical pattern of lower gastrointestinal origin with stromal minor sex-cord elements: A case report.

    PubMed

    Ueda, Taeko; Nakagawa, Hitomi; Hachisuga, Toru

    2014-12-01

    •We report a case of an ovarian mucinous cystadenoma that exhibited extensive sex-cord differentiation.•The ovarian tumor coincided with a uterine endometrial carcinoma.•The immunohistochemical pattern of mucinous epithelium of the ovarian tumor was suggestive of lower gastrointestinal origin.

  11. Oncocytic variant of malignant gastrointestinal neuroectodermal tumor: a potential diagnostic pitfall.

    PubMed

    Boland, Jennifer M; Folpe, Andrew L

    2016-11-01

    Malignant gastrointestinal neuroectodermal tumor (MGNET) is a very rare, aggressive malignant neoplasm that may occur in any location in the gastrointestinal tract. Malignant gastrointestinal neuroectodermal tumors typically consist of sheet-like to pseudopapillary proliferation of primitive-appearing epithelioid cells with a moderate amount of lightly eosinophilic cytoplasm, round nuclei and small nucleoli, often in association with osteoclast-like giant cells. By immunohistochemistry, these tumors show expression of S100 protein and SOX10, in the absence of expression of more specific melanocytic markers (eg, HMB45, Melan A). Genetically, malignant gastrointestinal neuroectodermal tumors are characterized by rearrangements of the EWSR1 or FUS genes with CREB1 or ATF1. We report a case of gastric malignant gastrointestinal neuroectodermal tumor occurring in a 46-year-old woman and showing striking oncocytic cytoplasmic change, a previously undescribed potential diagnostic pitfall. An initial needle biopsy showed large, eosinophilic cells with S100 protein and SOX10 expression and lacking expression of KIT, DOG1, Melan A, keratin, chromogranin, or smooth muscle actin, and was interpreted as representing a granular cell tumor. The subsequent excision specimen showed similar-appearing areas, but also contained small more primitive-appearing areas, lacking oncocytic change and having high nuclear grade and brisk mitotic activity. This resection specimen was initially diagnosed as a malignant granular cell tumor. However subsequent gene expression profiling studies showed an EWSR1-ATF1 fusion, confirmed with fluorescence in situ hybridization for EWSR1, and a final diagnosis of MGNET with oncocytic change was made. This case highlights a previously undescribed pitfall in the diagnosis of MGNET, oncocytic change, and suggests that MGNET should be included in the differential diagnosis for unusual oncocytic neoplasms of the gastrointestinal tract.

  12. Tumor Associated Stromal Cells Play a Critical Role on the Outcome of the Oncolytic Efficacy of Conditionally Replicative Adenoviruses

    PubMed Central

    Lopez, M. Verónica; Viale, Diego L.; Cafferata, Eduardo G. A.; Bravo, Alicia I.; Carbone, Cecilia; Gould, David; Chernajovsky, Yuti; Podhajcer, Osvaldo L.

    2009-01-01

    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. PMID:19337591

  13. Conservative Resectoscopic Surgery, Successful Delivery, and 60 Months of Follow-Up in a Patient with Endometrial Stromal Tumor with Sex-Cord-Like Differentiation.

    PubMed

    De Franciscis, Pasquale; Grauso, Flavio; Ambrosio, Domenico; Torella, Marco; Messalli, Enrico Michelino; Colacurci, Nicola

    2016-01-01

    Uterine tumors with sex-cord-like differentiation are extremely rare types of uterine stromal neoplasm. These tumors were classified into two groups with considerable practical relevance because clinical behaviour of uterine tumor resembling ovarian sex cord tumor (UTROSCT) differs widely from its closely related endometrial stromal tumors with sex-cord-like elements (ESTSCLE). Treatment and prognosis of these tumors are unresolved issues because of the exiguous number of reported cases. We describe a rare case of endometrial stromal tumor with sex-cord-like differentiation successfully treated by resectoscopic surgery and conservation of the uterus, in an infertile patient affected by metrorrhagia. This procedure resulted in a pregnancy immediately after treatment and in a successful delivery. During 60 months of follow-up no evidence of recurrence was observed.

  14. Conservative Resectoscopic Surgery, Successful Delivery, and 60 Months of Follow-Up in a Patient with Endometrial Stromal Tumor with Sex-Cord-Like Differentiation

    PubMed Central

    De Franciscis, Pasquale; Grauso, Flavio; Ambrosio, Domenico; Torella, Marco; Messalli, Enrico Michelino; Colacurci, Nicola

    2016-01-01

    Uterine tumors with sex-cord-like differentiation are extremely rare types of uterine stromal neoplasm. These tumors were classified into two groups with considerable practical relevance because clinical behaviour of uterine tumor resembling ovarian sex cord tumor (UTROSCT) differs widely from its closely related endometrial stromal tumors with sex-cord-like elements (ESTSCLE). Treatment and prognosis of these tumors are unresolved issues because of the exiguous number of reported cases. We describe a rare case of endometrial stromal tumor with sex-cord-like differentiation successfully treated by resectoscopic surgery and conservation of the uterus, in an infertile patient affected by metrorrhagia. This procedure resulted in a pregnancy immediately after treatment and in a successful delivery. During 60 months of follow-up no evidence of recurrence was observed. PMID:27213063

  15. Role of CXCL13-CXCR5 crosstalk between malignant neuroblastoma cells and Schwannian stromal cells in neuroblastic tumors.

    PubMed

    Del Grosso, Federica; Coco, Simona; Scaruffi, Paola; Stigliani, Sara; Valdora, Francesca; Benelli, Roberto; Salvi, Sandra; Boccardo, Simona; Truini, Mauro; Croce, Michela; Ferrini, Silvano; Longo, Luca; Tonini, Gian Paolo

    2011-07-01

    Neuroblastoma is a stroma-poor (SP) aggressive pediatric cancer belonging to neuroblastic tumors, also including ganglioneuroblastoma and ganglioneuroma, two stroma-rich (SR) less aggressive tumors. Our previous gene-expression profiling analysis showed a different CXCL13 mRNA expression between SP and SR tumors. Therefore, we studied 13 SP and 13 SR tumors by reverse transcription quantitative real-time PCR (RT-qPCR) and we found that CXCR5b was more expressed in SP than in SR and CXCL13 was predominantly expressed in SR tumors. Then, we isolated neuroblastic and Schwannian stromal cells by laser capture microdissection and we found that malignant neuroblasts express CXCR5b mRNA, whereas Schwannian stromal cells express CXCL13. Immunohistochemistry confirmed that stroma expresses CXCL13 but not CXCR5. To better understand the role of CXCL13 and CXCR5 in neuroblastic tumors we studied 11 neuroblastoma cell lines and we detected a heterogeneous expression of CXCL13 and CXCR5b. Interestingly, we found that only CXCR5b splice variant was expressed in both tumors and neuroblastoma lines, whereas CXCR5a was never detected. Moreover, we found that neuroblastoma cells expressing CXCR5 receptor migrate toward a source of recombinant CXCL13. Lastly, neuroblastoma cells induced to glial cell differentiation expressed CXCL13 mRNA and protein. The chemokine released in the culture medium was able to stimulate chemotaxis of LA1-5S neuroblastoma cells. Collectively, our data suggest that CXCL13 produced by stromal cells may contribute to the generation of an environment in which the malignant neuroblasts are retained, thus limiting the possible development of metastases in patients with SR tumor.

  16. An unusual association of malignant gastrointestinal neuroectodermal tumor (clear cell sarcoma-like) and Ewing sarcoma.

    PubMed

    Insabato, Luigi; Guadagno, Elia; Natella, Valentina; Somma, Anna; Bihl, Michel; Pizzolorusso, Antonio; Mainenti, Pier Paolo; Apice, Gaetano; Tornillo, Luigi

    2015-09-01

    Very recently a new designation of "Malignant Neuroectodermal Gastrointestinal Tumor" has been proposed for an aggressive form of neuroectodermal tumor with features similar to that of Clear Cell Sarcoma of Soft Tissue, however without a melanocytic differentiation. Also known as "clear cell sarcoma-like tumors of the gastrointestinal tract", these tumors show some features strongly suggesting an origin from a gastrointestinal neuroectodermal precursor cell unable to differentiate along the melanocytic lineage. They occur mainly in young and middle-aged adults, and have a poor prognosis with a high rate of liver and lymphnode metastases. Histologically they are composed of epithelioid or oval-to spindle cells with a sheet-like or nested pattern of growth, strongly positive for neural markers (S-100, SOX10, and vimentin) and negative for the melanocytic ones. EWSR1 gene rearrangements including EWSR1-ATF1 or EWSR1-CREB1 GENE fusions are typically assessed in these tumors. Here we report a case of malignant neuroectodermal gastrointestinal tumor which immunophenotypically unusually expressed FLI-1, occurring in a 29-year-old man with a previous medical history of Ewing sarcoma. We finally suggest that this case might be a further evidence of a link between these two entities.

  17. Evidence for a stromal-epithelial “lactate shuttle” in human tumors

    PubMed Central

    Lin, Zhao; Ertel, Adam; Flomenberg, Neal; Witkiewicz, Agnieszka K; Birbe, Ruth C; Howell, Anthony; Pavlides, Stephanos; Gandara, Ricardo; Pestell, Richard G; Sotgia, Federica

    2011-01-01

    Recently, we proposed a new mechanism for understanding the Warburg effect in cancer metabolism. In this new paradigm, cancer-associated fibroblasts undergo aerobic glycolysis, and extrude lactate to “feed” adjacent cancer cells, which then drives mitochondrial biogenesis and oxidative mitochondrial metabolism in cancer cells. Thus, there is vectorial transport of energy-rich substrates from the fibroblastic tumor stroma to anabolic cancer cells. A prediction of this hypothesis is that cancer-associated fibroblasts should express MCT4, a mono-carboxylate transporter that has been implicated in lactate efflux from glycolytic muscle fibers and astrocytes in the brain. To address this issue, we co-cultured MCF7 breast cancer cells with normal fibroblasts. Interestingly, our results directly show that breast cancer cells specifically induce the expression of MCT4 in cancer-associated fibroblasts; MCF7 cells alone and fibroblasts alone, both failed to express MCT4. We also show that the expression of MCT4 in cancer-associated fibroblasts is due to oxidative stress, and can be prevented by pre-treatment with the anti-oxidant N-acetyl-cysteine. In contrast to our results with MCT4, we see that MCT1, a transporter involved in lactate uptake, is specifically upregulated in MCF7 breast cancer cells when co-cultured with fibroblasts. Virtually identical results were also obtained with primary human breast cancer samples. In human breast cancers, MCT4 selectively labels the tumor stroma, e.g., the cancer-associated fibroblast compartment. Conversely, MCT1 was selectively expressed in the epithelial cancer cells within the same tumors. Functionally, we show that overexpression of MCT4 in fibroblasts protects both MCF7 cancer cells and fibroblasts against cell death, under co-culture conditions. Thus, we provide the first evidence for the existence of a stromal-epithelial lactate shuttle in human tumors, analogous to the lactate shuttles that are essential for the normal

  18. Endothelial Differentiation of Adipose Tissue-Derived Mesenchymal Stromal Cells in Glioma Tumors: Implications for Cell-Based Therapy

    PubMed Central

    Bagó, Juli R; Alieva, Maria; Soler, Carolina; Rubio, Núria; Blanco, Jerónimo

    2013-01-01

    Multipotent human adipose tissue mesenchymal stromal cells (hAMSCs) are promising therapy vehicles with tumor-homing capacity that can be easily modified to deliver cytotoxicity activating systems in the proximity of tumors. In a previous work, we observed that hAMSCs are very effective delivering cytotoxicity to glioma tumors. However, these results were difficult to reconcile with the relatively few hAMSCs surviving implantation. We use a bioluminescence imaging (BLI) platform to analyze the behavior of bioluminescent hAMSCs expressing HSV-tTK in a U87 glioma model and gain insight into the therapeutic mechanisms. Tumor-implanted hAMSCs express the endothelial marker PECAM1(CD31), integrate in tumor vessels and associate with CD133-expressing glioma stem cells (GSC). Inhibition of endothelial lineage differentiation in hAMSCs by Notch1 shRNA had no effect on their tumor homing and growth-promoting capacity but abolished the association of hAMSCs with tumor vessels and CD133+ tumor cells and significantly reduced their tumor-killing capacity. The current strategy allowed the study of tumor/stroma interactions, showed that tumor promotion and tumor-killing capacities of hAMSCs are based on different mechanisms. Our data strongly suggest that the therapeutic effectiveness of hAMSCs results from their association with special tumor vascular structures that also contain GSCs. PMID:23760448

  19. Stromal expression of Fer suppresses tumor progression in renal cell carcinoma and is a predictor of survival

    PubMed Central

    Mitsunari, Kensuke; Miyata, Yasuyoshi; Watanabe, Shin-Ichi; Asai, Akihiro; Yasuda, Takuji; Kanda, Shigeru; Sakai, Hideki

    2017-01-01

    Fps/Fes related (Fer) is a non-receptor tyrosine kinase that is expressed in fibroblasts, immune cells and endothelial cells. Fer serves an important pathological role in cell survival, angiogenesis and the immune system. However, the pathological role of Fer expression in the stromal cells surrounding renal cell carcinoma (RCC) has not been previously investigated. In the present study, immunohistochemical analysis of Fer was performed using the formalin-fixed tissue samples of 152 patients with RCC. The proliferative and apoptotic indices were used to represent the percentage of proliferation marker protein Ki-67- and cleaved caspase-3-positive cells, respectively. The microvessel density was defined as the number of cluster of differentiation (CD) 31-positively stained vessels/mm2. In addition, CD57+ and CD68+ cells were counted using semi-quantification of natural killer (NK) cells and macrophages. Fer expression in stromal cells was negatively associated with Fuhrman grade, pathological tumor stage and metastasis (P<0.001). Fer expression in stromal cells was negatively associated with CD68+ macrophage density, whereas it was positively associated with CD57+ NK cell density. Kaplan-Meier estimators indicated that decreased stromal Fer expression was a predictive marker of decreased cause-specific survival rate (P<0.001). Furthermore, low expression of Fer was identified as being an independent marker of decreased cause-specific survival using multivariate analysis (hazard ratio, 7.4; 95% confidence interval, 1.7–33.0; P<0.001). The results of the present study suggested that low Fer expression in stromal cells is associated with increased malignant aggressiveness and decreased survival in patients with RCC. CD57+ NK cell and CD68+ macrophage regulation in cancer-stromal tissue is considered to affect RCC pathology. PMID:28356966

  20. Genome-Wide Transcriptome Profiling of the Neoplastic Giant Cell Tumor of Bone Stromal Cells by RNA Sequencing.

    PubMed

    Lau, Carol P Y; Kwok, Jamie S L; Tsui, Joseph C C; Huang, Lin; Yang, Kevin Y; Tsui, Stephen K W; Kumta, Shekhar Madhukar

    2016-11-15

    Giant cell tumor of bone (GCTB) is the most common non-malignant primary bone tumor reported in Hong Kong. Failure of treatment in advanced GCTB with aggressive local recurrence remains a clinical challenge. In order to reveal the molecular mechanism underlying the pathogenesis of this tumor, we aimed to examine the transcriptome profiling of the neoplastic stromal cells of GCTB in this study. RNA-sequencing was performed on three GCTB stromal cell samples and one bone marrow-derived MSC sample and 174 differentially expressed genes (DEGs) were identified between these two cell types. The top five up-regulated genes are SPP1, F3, TSPAN12, MMP13, and LGALS3BP and further validated by qPCR and Western Blotting. Knockdown of SPP1 was found to induce RUNX2 and OPG expression in GCTB stromal cells but not the MSCs. Ingenuity pathway analysis (IPA) of the 174 DEGs revealed significant alternations in 23 pathways; variant calling analysis revealed 1915 somatic variants of 384 genes with high or moderate impacts. Interestingly, four canonical pathways were found overlapping in both analyses; from which VEGFA, CSF1, PLAUR, and F3 genes with somatic mutation were found up-regulated in GCTB stromal cells. The STRING diagram showed two main clusters of the DEGs; one cluster of histone genes that are down-regulated in GCTB samples and another related to osteoblast differentiation, angiogenesis, cell cycle progression, and tumor growth. The DEGs and somatic mutations found in our study warrant further investigation and validation, nevertheless, our study add new insights in the search for new therapeutic targets in treating GCTB. J. Cell. Biochem. 9999: 1-12, 2016. © 2016 Wiley Periodicals, Inc.

  1. [Abberant methylation of p16, HIC1, N33 and GSTP1 genes in tumor epitelium and tumor-associated stromal cells of prostate cancer].

    PubMed

    Kekeeva, T V; Popova, O P; Shegaĭ, P V; Alekseev, B Ia; Adnreeva, Iu Iu; Zaletaev, D V; Nemtsova, M V

    2007-01-01

    The methylation status of four genes significant in prostate carcinogenesis p16, HIC1, N33 and GSTP1, were evaluated using quantitative methylationsensitive polymerase chain reaction. Tumor epithelia, tumor-associated stroma, normal epithelia, foci of PIN and benign prostate hyperplasia, and stroma adjacent to tumor tissues were isolated from whole-mount prostatectomy specimens of patients with localized prostate cancer by using laser capture microdissection. We found high levels of gene methylation in the tumor epithelium and tumor-associated stromal cells and some methylation in both hyperplastic epithelium and stromal cells in normal-appearing tissues located adjacent to tumors. Promoter methylation in the non-neoplastic cells of the prostate tumor microenvironment may play an important role in cancer development and progression. We examined the promoter methylation status of pl6, HIC1, N33 and GSTP1 in prostate biopsy fragments and prostate tissues after radical prostatectomy from patients with adenocarcinoma without laser capture microdissection. Methylation frequencies of all genes in tumor samples were considerably lower than frequencies in microdissected tumour samples (HIC1, 71 versus 89%; p16, 22 versus 78%; GSTP1, 32 versus 100%; N33, 20 versus 33%). The laser capture microdissection is required procedure in methylation studies taking into account multifocality and heterogenity of prostate cancer tissue.

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

    PubMed

    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.

  3. A microfluidic co-culture system to monitor tumor-stromal interactions on a chip

    PubMed Central

    Menon, Nishanth V.; Cao, Bin; Lim, Mayasari; Kang, Yuejun

    2014-01-01

    The living cells are arranged in a complex natural environment wherein they interact with extracellular matrix and other neighboring cells. Cell-cell interactions, especially those between distinct phenotypes, have attracted particular interest due to the significant physiological relevance they can reveal for both fundamental and applied biomedical research. To study cell-cell interactions, it is necessary to develop co-culture systems, where different cell types can be cultured within the same confined space. Although the current advancement in lab-on-a-chip technology has allowed the creation of in vitro models to mimic the complexity of in vivo environment, it is still rather challenging to create such co-culture systems for easy control of different colonies of cells. In this paper, we have demonstrated a straightforward method for the development of an on-chip co-culture system. It involves a series of steps to selectively change the surface property for discriminative cell seeding and to induce cellular interaction in a co-culture region. Bone marrow stromal cells (HS5) and a liver tumor cell line (HuH7) have been used to demonstrate this co-culture model. The cell migration and cellular interaction have been analyzed using microscopy and biochemical assays. This co-culture system could be used as a disease model to obtain biological insight of pathological progression, as well as a tool to evaluate the efficacy of different drugs for pharmaceutical studies. PMID:25553194

  4. Spectrophotometric Determination of the Characteristics of Stromal and Parenchymal Components of Colon Tumors

    NASA Astrophysics Data System (ADS)

    Motevich, I. G.; Strekal, N. D.; Shulha, A. V.; Maskevich, S. A.

    2016-05-01

    We consider the dependence of the spectral properties of eosin and hematoxylin (dyes routinely used in histology as contrast agents) on their localization in biological tissues with different levels of pathology: benign and malignant neoplasms and sigmoid colonic crypts. We have analyzed the fluorescent images and fluorescence spectra of the parenchyma and stromal elements. We have established that on going from physiologically normal cells to tumor cells, the contribution to the absorption cross section of histologic sections due to hematoxylin increases. In pathologically altered cells in a colonic crypt, we observe a hypsochromic effect in the fluorescence spectra of the samples with appreciable quenching of the fluorescence, while in the model systems the reverse effect occurs: a shift of the fluorescence maximum toward the red region. We discuss the influence on the indicated effects from local pH and the polarity of the dye environment in the model systems and histologic sections. As the systems modeling the polarity and acidity of the biological media, we use aqueous solutions of the dyes with different pH values and synthetic polyelectrolytes.

  5. The pro-inflammatory peptide LL-37 promotes ovarian tumor progression through recruitment of multipotent mesenchymal stromal cells

    PubMed Central

    Coffelt, Seth B.; Marini, Frank C.; Watson, Keri; Zwezdaryk, Kevin J.; Dembinski, Jennifer L.; LaMarca, Heather L.; Tomchuck, Suzanne L.; zu Bentrup, Kerstin Honer; Danka, Elizabeth S.; Henkle, Sarah L.; Scandurro, Aline B.

    2009-01-01

    Bone marrow-derived mesenchymal stem cells or multipotent mesenchymal stromal cells (MSCs) have been shown to engraft into the stroma of several tumor types, where they contribute to tumor progression and metastasis. However, the chemotactic signals mediating MSC migration to tumors remain poorly understood. Previous studies have shown that LL-37 (leucine, leucine-37), the C-terminal peptide of human cationic antimicrobial protein 18, stimulates the migration of various cell types and is overexpressed in ovarian, breast, and lung cancers. Although there is evidence to support a pro-tumorigenic role for LL-37, the function of the peptide in tumors remains unclear. Here, we demonstrate that neutralization of LL-37 in vivo significantly reduces the engraftment of MSCs into ovarian tumor xenografts, resulting in inhibition of tumor growth as well as disruption of the fibrovascular network. Migration and invasion experiments conducted in vitro indicated that the LL-37-mediated migration of MSCs to tumors likely occurs through formyl peptide receptor like-1. To assess the response of MSCs to the LL-37-rich tumor microenvironment, conditioned medium from LL-37-treated MSCs was assessed and found to contain increased levels of several cytokines and pro-angiogenic factors compared with controls, including IL-1 receptor antagonist, IL-6, IL-10, CCL5, VEGF, and matrix metalloproteinase-2. Similarly, Matrigel mixed with LL-37, MSCs, or the combination of the two resulted in a significant number of vascular channels in nude mice. These data indicate that LL-37 facilitates ovarian tumor progression through recruitment of progenitor cell populations to serve as pro-angiogenic factor-expressing tumor stromal cells. PMID:19234121

  6. The pro-inflammatory peptide LL-37 promotes ovarian tumor progression through recruitment of multipotent mesenchymal stromal cells.

    PubMed

    Coffelt, Seth B; Marini, Frank C; Watson, Keri; Zwezdaryk, Kevin J; Dembinski, Jennifer L; LaMarca, Heather L; Tomchuck, Suzanne L; Honer zu Bentrup, Kerstin; Danka, Elizabeth S; Henkle, Sarah L; Scandurro, Aline B

    2009-03-10

    Bone marrow-derived mesenchymal stem cells or multipotent mesenchymal stromal cells (MSCs) have been shown to engraft into the stroma of several tumor types, where they contribute to tumor progression and metastasis. However, the chemotactic signals mediating MSC migration to tumors remain poorly understood. Previous studies have shown that LL-37 (leucine, leucine-37), the C-terminal peptide of human cationic antimicrobial protein 18, stimulates the migration of various cell types and is overexpressed in ovarian, breast, and lung cancers. Although there is evidence to support a pro-tumorigenic role for LL-37, the function of the peptide in tumors remains unclear. Here, we demonstrate that neutralization of LL-37 in vivo significantly reduces the engraftment of MSCs into ovarian tumor xenografts, resulting in inhibition of tumor growth as well as disruption of the fibrovascular network. Migration and invasion experiments conducted in vitro indicated that the LL-37-mediated migration of MSCs to tumors likely occurs through formyl peptide receptor like-1. To assess the response of MSCs to the LL-37-rich tumor microenvironment, conditioned medium from LL-37-treated MSCs was assessed and found to contain increased levels of several cytokines and pro-angiogenic factors compared with controls, including IL-1 receptor antagonist, IL-6, IL-10, CCL5, VEGF, and matrix metalloproteinase-2. Similarly, Matrigel mixed with LL-37, MSCs, or the combination of the two resulted in a significant number of vascular channels in nude mice. These data indicate that LL-37 facilitates ovarian tumor progression through recruitment of progenitor cell populations to serve as pro-angiogenic factor-expressing tumor stromal cells.

  7. Activating mutation of the stimulatory G protein (gsp) as a putative cause of ovarian and testicular human stromal Leydig cell tumors.

    PubMed

    Fragoso, M C; Latronico, A C; Carvalho, F M; Zerbini, M C; Marcondes, J A; Araujo, L M; Lando, V S; Frazzatto, E T; Mendonca, B B; Villares, S M

    1998-06-01

    Activating mutations of the G protein genes have been associated with the development of several endocrine neoplasms. Such activating mutations, gip2, affecting the alpha-subunit of the G alpha i2 protein were previously described by a single group in 30% of ovarian sex cord stromal tumors. Other activating mutations of the alpha-subunit of the Gs (gsp) have been identified in GH-secreting and nonfunctioning pituitary tumors, autonomous thyroid adenomas, and all affected McCune-Albright tissues, but not in sex cord stromal tumors. In the present study, we investigated the presence of gip2 and gsp mutations in 14 human sex cord stromal tumors. Six Leydig cell tumors (4 ovaries and 2 testes), 2 thecomas, 2 granulosa cell tumors, 3 androblastomas, and 1 gonadoblastoma (sex cord and germ cell) were included in this study. Genomic DNA was obtained from either fresh-frozen tumor tissues or paraffin-embedded sections and in some cases from blood samples. Using PCR, denaturing gradient gel electrophoresis, and direct sequencing, we detected 4 tumors (66.6%) with the gsp mutation (R201C) in our series of ovarian and testicular Leydig cell tumors. In contrast, no gip2 mutations were found in any of the sex cord stromal tumors studied. In conclusion, our findings suggest that the putative oncogene gsp may play a significant role in the molecular mechanism of these tumors.

  8. Inflammatory Myofibroblastic Tumor of the Breast Coexisting with Pseudoangiomatous Stromal Hyperplasia

    PubMed Central

    Talu, Canan Kelten; Çakır, Yasemin; Hacıhasanoğlu, Ezgi; Leblebici, Cem; Aksoy, Şefika; Nazlı, Mehmet Ali

    2016-01-01

    Inflammatory myofibroblastic tumors (IMTs) are uncommon breast lesions that consist of spindle cells accompanied by plasma cell-rich inflammatory infiltration, which may mimic breast cancer clinico-radiologically. A woman aged 38 years with a breast mass was referred to our general surgery clinic. The physical examination revealed a mass with irregular borders in the upper outer quadrant of the left breast. In mammography, the lesion was 15 mm in diameter with a spheric form and high density. Ultrasonographically, the mass was solid, heterogeneous, and hypoechoic with posterior enhancement. Histopathologic examination of a core needle biopsy revealed a proliferation of spindle cells with eosinophilic cytoplasm and mild nuclear atypia, which showed negative immunostaining for pancytokeratin, HMWCK, CAM5.2, p63, CD34, β-catenin, and ALK but diffuse positivity for smooth muscle alpha (SMA). The lesion was reported as a “spindle cell lesion” and excision with clear margins was recommended. In the lumpectomy specimen, the lesion consisted of spindle cells that formed fascicles and infiltrated the surrounding breast parenchyma. Lymphocytes and plasmocytes scattered among spindle cells were noted. Necrosis, increased mitotic activity, nuclear pleomorphism and hyperchromasia were not detected. Immunohistochemical findings were the same in the core needle biopsy. The Ki-67 proliferation index was below 5%. With these findings, differential diagnoses were ruled out and the tumor was reported as IMT. In close proximity to this lesion, areas of columnar cell lesion with atypia and surrounding pseudoangiomatous stromal hyperplasia were seen. Patient has a follow-up of 16 months without recurrence. PMID:28331757

  9. Photodynamic Therapy Using Endogenous Photosensitization for Gastrointestinal Tumors

    PubMed Central

    Webber, John; Kessel, David; Fromm, David

    1997-01-01

    Photodynamic therapy (PDT) is a novel approach in the treatment of carcinomas of the gastrointestinal tract. This review defines PDT, discusses means of photosensitization and considers the mechanisms by which PDT causes cell death of the target tissue while at the same time avoid damage to normal tissues. Additional considerations include the time of PDT application, activation of the photosensitizer, effectiveness and toxicity of PDT, potential need for additional modalities of treatment and concludes with application of PDT principals to the early detection of malignancy. Data regarding the long term effectiveness of PDT for digestive tract adenocarcinomas are lacking because this field is still in its infancy.

  10. What Are the Risk Factors for Gastrointestinal Carcinoid Tumors?

    MedlinePlus

    ... Testing: What You Need to Know . Race and gender Carcinoid tumors are more common among African Americans ... would like to unsubscribe/opt out from our communications, please follow this link: http://www.cancer.org/ ...

  11. Stromal progenitor cells from endogenous adipose tissue contribute to pericytes and adipocytes that populate the tumor microenvironment.

    PubMed

    Zhang, Yan; Daquinag, Alexes C; Amaya-Manzanares, Felipe; Sirin, Olga; Tseng, Chieh; Kolonin, Mikhail G

    2012-10-15

    Epidemiologic studies associate cancer with obesity, but the pathophysiologic connections remain obscure. In this study, we show that obesity facilitates tumor growth in mice irrespective of concurrent diet, suggesting a direct effect of excess white adipose tissue (WAT). When transplanted into mice, adipose stromal cells (ASC) can serve as perivascular adipocyte progenitors that promote tumor growth, perhaps helping explain the obesity-cancer link. In developing this hypothesis, we showed that ASCs are expanded in obesity and that they traffic from endogenous WAT to tumors in several mouse models of cancer. Strikingly, a comparison of circulating and tumor-infiltrating cell populations in lean, and obese mice revealed that cancer induces a six-fold increase of ASC frequency in the systemic circulation. We obtained evidence that ASCs mobilized in this way can be recruited into tumors, where they can be incorporated into blood vessels as pericytes and they can differentiate into adipocytes in an obesity-dependent manner. Extending this evidence, we found that increased tumor vascularization (reflected by changes in tumor vascular morphology and a two-fold increase in vascular density) was associated with intratumoral adipocytes and elevated proliferation of neighboring malignant cells. Taken together, our results suggest that ASCs recruited from endogenous adipose tissue can be recruited by tumors to potentiate the supportive properties of the tumor microenvironment.

  12. Fluorescence spectroscopy of gastrointestinal tumors using δ-ALA

    NASA Astrophysics Data System (ADS)

    Borisova, E. G.; Vladimirov, B. G.; Angelov, I. G.; Avramov, L. A.

    2007-03-01

    In the recent study delta-aminolevulinic acid/Protoporphyrin IX (δ-ALA/PpIX) is used as fluorescent marker for dysplasia and tumor detection in esophagus and stomach. The δ-ALA is administered per os six hours before measurements at dose 20mg/kg weight. High-power light-emitting diode at 405 nm is used as an excitation source. Special opto-mechanical device is built to use the light guide of standard video-endoscopic system (Olimpus Corp.). Through endoscopic instrumental channel a fiber is applied to return information about fluorescence to microspectrometer (USB4000, OceanOptics Inc.). The fluorescence detected from tumor sites has very complex spectral origins. It consists of autofluorescence, fluorescence from exogenous fluorophores and re-absorption from the chromophores accumulated in the tissue investigated. Mucosa autofluorescence lies at 450-600 nm region. The fluorescence of PpIX is clearly pronounced at the 630-710 nm region. Deep minima in the tumor fluorescence signals are observed in the region 540-575 nm, related to hemoglobin re-absorption. Such high hemoglobin content is an indication of the tumors neovascularisation and it is clearly pronounced in all dysplastic and tumor sites investigated. The lack of fluorescence peaks in the red spectral area for normal mucosa is an indication for selective accumulation of δ-ALA/PpIX only in abnormal sites and gives high contrast when lesion borders are determined from clinicians during video observation in the process of diagnostic procedure. Very good correlation between fluorescence signals and histology examination results of the lesions investigated is achieved.

  13. Wide-field endoscopic fluorescence imaging for gastrointestinal tumor detection with glucose analogue

    NASA Astrophysics Data System (ADS)

    He, Yun; Qu, Yawei; Bai, Jing; Liu, Haifeng

    2014-05-01

    The lack of functional information and targeted imaging in conventional white-light endoscopy leads to a high miss-rate of gastrointestinal tumor. The combination of near-infrared fluorescence imaging and endoscopy presents a promising approach. Here we introduce a new endoscopy method employing a home-made flexible wide-field epi-fluorescence endoscope, that can be inserted through the biopsy channel of a gastrointestinal endoscope, with the glucose analogue 2- DeoxyGlucosone as the near-infrared fluorescent probe. System characterization indicates a good sensitivity and linearity over a large field of view. Its capability of tumor identification and location is demonstrated with in-vivo imaging of xenografted tumor model.

  14. Quantifying local heterogeneity via morphologic scale: Distinguishing tumoral from stromal regions

    PubMed Central

    Janowczyk, Andrew; Chandran, Sharat; Madabhushi, Anant

    2013-01-01

    Introduction: The notion of local scale was introduced to characterize varying levels of image detail so that localized image processing tasks could be performed while simultaneously yielding a globally optimal result. In this paper, we have presented the methodological framework for a novel locally adaptive scale definition, morphologic scale (MS), which is different from extant local scale definitions in that it attempts to characterize local heterogeneity as opposed to local homogeneity. Methods: At every point of interest, the MS is determined as a series of radial paths extending outward in the direction of least resistance, navigating around obstructions. Each pixel can then be directly compared to other points of interest via a rotationally invariant quantitative feature descriptor, determined by the application of Fourier descriptors to the collection of these paths. Results: Our goal is to distinguish tumor and stromal tissue classes in the context of four different digitized pathology datasets: prostate tissue microarrays (TMAs) stained with hematoxylin and eosin (HE) (44 images) and TMAs stained with only hematoxylin (H) (44 images), slide mounts of ovarian H (60 images), and HE breast cancer (51 images) histology images. Classification performance over 50 cross-validation runs using a Bayesian classifier produced mean areas under the curve of 0.88 ± 0.01 (prostate HE), 0.87 ± 0.02 (prostate H), 0.88 ± 0.01 (ovarian H), and 0.80 ± 0.01 (breast HE). Conclusion: For each dataset listed in Table 3, we randomly selected 100 points per image, and using the procedure described in Experiment 1, we attempted to separate them as belonging to stroma or epithelium. PMID:23766944

  15. [Gastrointestinal stromal tumours (GIST)--development in pathology, surgery and medical therapy. Developed during the 10th German GIST-meeting, Göttingen].

    PubMed

    Agaimy, A; Bauer, S; Beham, A; Bertolini, J; Haller, F; Koschny, R; Maier, J; Montemurro, M; Perez, D; Schaefer, I-M; Schildhaus, H-U; Wurst, C; Cameron, S

    2015-03-01

    The first description of ligand-independent activating mutations in the KIT gene, which encodes the tyrosine-kinase KIT, greatly improved our understanding of gastrointestinal stromal tumour (GIST) biology. The therapeutic success in GIST has made tyrosine kinase inhibitors a "paradigm of targeted therapy". Deciphering resistance mechanisms in GIST has had implications for many other kinase-driven cancers. To exchange current knowledge within the field of GIST, the German GIST Meeting has taken place for now 10 years, traditionally in Göttingen. Subjects discussed include clinical diagnostics, pathology, surgery, and medical therapy. The following presentation gives an overview of the last meeting held in December 2013, including distinctive features in GIST and current data on the different topics.

  16. Successful treatment of bleeding large duodenal gastrointestinal stromal tumour in a patient under dual antiplatelet therapy after recent drug-eluting coronary stent implantation

    PubMed Central

    Fukuyama, Keita; Fujikawa, Takahisa; Kuramitsu, Shoichi; Tanaka, Akira

    2014-01-01

    We report a case of a 69-year-old man who started dual antiplatelet therapy (APT) with aspirin and clopidogrel after recent implantation of drug-eluting coronary stent and developed massive bleeding due to large duodenal gastrointestinal stromal tumour (GIST). Following endoscopic haemostasis and discontinuation of dual APT, neoadjuvant chemotherapy with imatinib was started under continuation of ‘single’ APT with aspirin. A good chemotherapeutic response was achieved without recurrence of bleeding, and subsequent less invasive surgical resection of the tumour was performed, while preoperative single APT was continued for prevention of stent thrombosis. The patient recovered well without any thromboembolic or bleeding events. Neoadjuvant imatinib therapy and subsequent less invasive surgery under continuation of APT is one of the preferred approaches for patients with duodenal GIST with severe thromboembolic comorbidities, as in the current case. PMID:24777088

  17. [Gastro-intestinal neuroectodermal tumor (GNET): A case report of a small intestine tumor with hepatic metastases].

    PubMed

    Kervarrec, Thibault; Lecointre, Claire; Kerdraon, Rémy; Bens, Guido; Piquard, Arnaud; Michenet, Patrick

    2015-12-01

    The gastro-intestinal neuroectodermal tumor (GNET) is a rare sarcoma of the digestive tract, which was recently recognised. The knowledge of the morphological, immunohistochemical and molecular diagnostic criteria is necessary to not mistake it for the metastasis of a melanoma or for another sarcoma of the digestive tract as the gastro-intestinal clear cells sarcoma or the malignant peripheral nervous system tumor (MPNST). We report the case of a 41-year-old patient with a GNET of the small intestine with hepatic metastasis. The histological examination showed a diffuse proliferation of epithelioid cells, which only express PS100. The presence EWSR1-ATF1 gene fusions with any melanocytic differentiation leads to the diagnosis of GNET.

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

    SciTech Connect

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

    2011-05-01

    Purpose: Head-and-neck squamous cell carcinoma (HNSCC) is the fifth most common malignancy worldwide. Alcohol use and tobacco use are the most established risk factors; however, human papilloma virus (HPV) infection is a major risk factor for a subset of HNSCCs. Although HPV-positive tumors typically present at a more advanced stage at diagnosis, they are associated with a better prognosis. Tumor hypoxia confers poor prognosis and treatment failure, but direct tumor oxygen measurement is challenging. Endogenous markers of hypoxia (EMHs) have been proposed but have not replicated the prognostic utility of direct oxygen measurement. The expression of endogenous markers of hypoxia may be influenced by oxygen-independent factors, such as the HPV status of the tumor. Methods and Materials: Consecutive cases of locally advanced HNSCC, treated with a uniform regimen of combined radiotherapy and chemotherapy, were identified. Tissue microarrays were assembled from triplicate 0.6-mm cores of archived tumor tissue. HPV status was inferred from semiquantitative p16 immunostaining and directly measured by use of HPV-specific chromogenic in situ hybridization and polymerase chain reaction. Automated quantitative fluorescent immunohistochemistry was conducted to measure epithelial and stromal expression of carbonic anhydrase IX (CAIX) and glucose transporter 1 (GLUT1). Results: High stromal CAIX expression was associated with significantly reduced overall survival (p = 0.03) in patients with p16-negative tumors. Conclusions: This is the first study to use quantitative immunohistochemistry to examine endogenous markers of hypoxia stratified by tumor p16/HPV status. Assessment of CAIX expression in p16-negative HNSCC could identify patients with the least favorable prognosis and inform therapeutic strategies.

  19. CAR-T cell therapy in gastrointestinal tumors and hepatic carcinoma: From bench to bedside

    PubMed Central

    Zhang, Qi; Zhang, Zimu; Peng, Meiyu; Fu, Shuyu; Xue, Zhenyi; Zhang, Rongxin

    2016-01-01

    ABSTRACT The chimeric antigen receptor (CAR) is a genetically engineered receptor that combines a scFv domain, which specifically recognizes the tumor-specific antigen, with T cell activation domains. CAR-T cell therapies have demonstrated tremendous efficacy against hematologic malignancies in many clinical trials. Recent studies have extended these efforts to the treatment of solid tumors. However, the outcomes of CAR-T cell therapy for solid tumors are not as remarkable as the outcomes have been for hematologic malignancies. A series of hurdles has arisen with respect to CAR-T cell-based immunotherapy, which needs to be overcome to target solid tumors. The major challenge for CAR-T cell therapy in solid tumors is the selection of the appropriate specific antigen to demarcate the tumor from normal tissue. In this review, we discuss the application of CAR-T cells to gastrointestinal and hepatic carcinomas in preclinical and clinical research. Furthermore, we analyze the usefulness of several specific markers in the study of gastrointestinal tumors and hepatic carcinoma. PMID:28123893

  20. CAR-T cell therapy in gastrointestinal tumors and hepatic carcinoma: From bench to bedside.

    PubMed

    Zhang, Qi; Zhang, Zimu; Peng, Meiyu; Fu, Shuyu; Xue, Zhenyi; Zhang, Rongxin

    2016-01-01

    The chimeric antigen receptor (CAR) is a genetically engineered receptor that combines a scFv domain, which specifically recognizes the tumor-specific antigen, with T cell activation domains. CAR-T cell therapies have demonstrated tremendous efficacy against hematologic malignancies in many clinical trials. Recent studies have extended these efforts to the treatment of solid tumors. However, the outcomes of CAR-T cell therapy for solid tumors are not as remarkable as the outcomes have been for hematologic malignancies. A series of hurdles has arisen with respect to CAR-T cell-based immunotherapy, which needs to be overcome to target solid tumors. The major challenge for CAR-T cell therapy in solid tumors is the selection of the appropriate specific antigen to demarcate the tumor from normal tissue. In this review, we discuss the application of CAR-T cells to gastrointestinal and hepatic carcinomas in preclinical and clinical research. Furthermore, we analyze the usefulness of several specific markers in the study of gastrointestinal tumors and hepatic carcinoma.

  1. MiRNA profiling of gastrointestinal stromal tumors by next-generation sequencing.

    PubMed

    Gyvyte, Ugne; Juzenas, Simonas; Salteniene, Violeta; Kupcinskas, Juozas; Poskiene, Lina; Kucinskas, Laimutis; Jarmalaite, Sonata; Stuopelyte, Kristina; Steponaitiene, Ruta; Hemmrich-Stanisak, Georg; Hübenthal, Matthias; Link, Alexander; Franke, Sabine; Franke, Andre; Pangonyte, Dalia; Lesauskaite, Vaiva; Kupcinskas, Limas; Skieceviciene, Jurgita

    2017-03-29

    Deregulation of miRNAs has been observed virtually in all major types of cancer, whereas the miRNA signature in GIST is not well characterized yet. In this study the first high-throughput miRNA profiling of 15 paired GIST and adjacent normal tissue samples was performed using small RNA-seq approach and differentially expressed miRNAs as well as isomiRNAs were defined. Highly significantly deregulated miRNAs were selected for validation by Taq-Man low-density array in replication group of 40 paired samples. Validated miRNAs were further subjected to enrichment analysis, which revealed significantly enriched KEGG pathways in the main GIST associated pathways. Further, we used an integrated analysis of miRNA-mRNA correlations for KIT and PDGFRA target genes and found a significant correlation between all of the enriched miRNAs and their target gene KIT. Results of the phenotype analysis showed miR-509-3p to be up-regulated in epithelioid and mixed cell types compared to spindle type, whereas miR-215-5p showed negative correlation with risk grade of GIST. These data reveal a detailed miRNA profile of GIST and highlight new candidates that may be important in the development of malignant disease.

  2. Study on the Evolution of Genes Mutation Related With Gastrointestinal Stromal Tumors

    ClinicalTrials.gov

    2012-01-05

    Full Gene Sequences of c-KIT、PDGFRA and DOG1 Are Analyzed With the Screening-sequencing Approach; Investigate the Characteristics and Variations Associated With the Different Gene Mutations of c-KIT、PDGFRA and DOG1 in GIST Patients

  3. Prognostic values of DLK1 for surgery and imatinib mesylate adjuvant therapy in gastrointestinal stromal tumors

    PubMed Central

    Xu, Jia; Wang, Ming; Zhang, Zizhen; Zhao, Wenyi; Wang, Chaojie; Tu, Lin; Zhang, Yeqian; Cao, Hui

    2016-01-01

    The Delta-like 1 homolog (DLK1) gene is a paternal imprinting gene located on human chromosome 14q32, a site associated with frequent chromosomal mutations in GIST. The expression level of DLK1 is closely associated with the outcome of tumours. However, no study has reported the DLK1 expression in GIST. Here, we demonstrated that DLK1 showed low expression in GIST patients with low risk according to the modified National Institute of Health (NIH) criteria. With increasing tumour risk level, DLK1 gene and protein expression levels gradually increased. In the test cohort, tissue microarray data showed that DLK1 protein expression was significantly associated with tumour size, mitotic figure count, NIH risk level, and Ki67 expression. In terms of either disease-free survival (DFS) or overall survival (OS), the long-term outcome was significantly better in DLK1-negative patients than in DLK1-positive patients. Univariate and multivariate analyses suggested that DLK1 expression was an independent risk factor influencing tumour DFS. Additionally, for intermediate/high-risk GIST patients received postoperative IM adjuvant therapy, Kaplan-Meier analysis showed that IM adjuvant therapy was associated with a better outcome in DLK1-negative patients than in DLK1-positive patients. All of the above results were verified in the validation cohort. Taken together, DLK1 is a promising prognostic biomarker for GISTs that may help to predict surgical outcomes and guide adjuvant IM therapy. PMID:27904782

  4. Glioblastoma Therapy with Cytotoxic Mesenchymal Stromal Cells Optimized by Bioluminescence Imaging of Tumor and Therapeutic Cell Response

    PubMed Central

    Alieva, Maria; Bagó, Juli R.; Aguilar, Elisabet; Soler-Botija, Carolina; Vila, Olaia F.; Molet, Joan; Gambhir, Sanjiv S.; Rubio, Nuria; Blanco, Jerónimo

    2012-01-01

    Genetically modified adipose tissue derived mesenchymal stromal cells (hAMSCs) with tumor homing capacity have been proposed for localized therapy of chemo- and radiotherapy resistant glioblastomas. We demonstrate an effective procedure to optimize glioblastoma therapy based on the use of genetically modified hAMSCs and in vivo non invasive monitoring of tumor and therapeutic cells. Glioblastoma U87 cells expressing Photinus pyralis luciferase (Pluc) were implanted in combination with hAMSCs expressing a trifunctional Renilla reniformis luciferase-red fluorescent protein-thymidine kinase reporter in the brains of SCID mice that were subsequently treated with ganciclovir (GCV). The resulting optimized therapy was effective and monitoring of tumor cells by bioluminescence imaging (BLI) showed that after 49 days GCV treatment reduced significantly the hAMSC treated tumors; by a factor of 104 relative to controls. Using a Pluc reporter regulated by an endothelial specific promoter and in vivo BLI to image hAMSC differentiation we gained insight on the therapeutic mechanism. Implanted hAMSCs homed to tumor vessels, where they differentiated to endothelial cells. We propose that the tumor killing efficiency of genetically modified hAMSCs results from their association with the tumor vascular system and should be useful vehicles to deliver localized therapy to glioblastoma surgical borders following tumor resection. PMID:22529983

  5. Caveolin-1 and mitochondrial SOD2 (MnSOD) function as tumor suppressors in the stromal microenvironment

    PubMed Central

    Trimmer, Casey; Sotgia, Federica; Whitaker-Menezes, Diana; Balliet, Renee M; Eaton, Gregory; Martinez-Outschoorn, Ubaldo E; Pavlides, Stephanos; Howell, Anthony; Iozzo, Renato V; Pestell, Richard G; Scherer, Philipp E

    2011-01-01

    We have recently proposed a new model for understanding tumor metabolism, termed: “The Autophagic Tumor Stroma Model of Cancer Metabolism”. In this new paradigm, catabolism (autophagy) in the tumor stroma fuels the anabolic growth of aggressive cancer cells. Mechanistically, tumor cells induce autophagy in adjacent cancer-associated fibroblasts via the loss of caveolin-1 (Cav-1), which is sufficient to promote oxidative stress in stromal fibroblasts. To further test this hypothesis, here we created human Cav-1 deficient immortalized fibroblasts using a targeted sh-RNA knock-down approach. Relative to control fibroblasts, Cav-1 deficient fibroblasts dramatically promoted tumor growth in xenograft assays employing an aggressive human breast cancer cell line, namely MDA-MB-231 cells. Co-injection of Cav-1 deficient fibroblasts, with MDA-MB-231 cells, increased both tumor mass and tumor volume by ∼4-fold. Immuno-staining with CD31 indicated that this paracrine tumor promoting effect was clearly independent of angiogenesis. Mechanistically, proteomic analysis of these human Cav-1 deficient fibroblasts identified >40 protein biomarkers that were upregulated, most of which were associated with (i) myofibroblast differentiation or (ii) oxidative stress/hypoxia. In direct support of these findings, the tumor promoting effects of Cav-1 deficient fibroblasts could be functionally suppressed (nearly 2-fold) by the recombinant overexpression of SOD2 (superoxide dismutase 2), a known mitochondrial enzyme that de-activates superoxide, thereby reducing mitochondrial oxidative stress. In contrast, cytoplasmic soluble SOD1 had no effect, further highlighting a specific role for mitochondrial oxidative stress in this process. In summary, here we provide new evidence directly supporting a key role for a loss of stromal Cav-1 expression and oxidative stress in cancerassociated fibroblasts, in promoting tumor growth, which is consistent with “The Autophagic Tumor Stroma Model of

  6. Promotion of gastrointestinal tract tumors in animals: dietary factors.

    PubMed Central

    Newberne, P M; Schrager, T

    1983-01-01

    The biological mode of action of tumor promoters, exemplified by the phorbol esters, is a subject of intensive study in a number of laboratories. A few investigators have recently begun to examine the role of dietary nutrients in tumor promotion, but the available data are sparse and interpretation difficult. A few examples are provided to indicate that some nutrients may be important in the promotion of cancer. However, the fine dividing line between effects on initiation or on promotion, so clearly shown in the mouse two-stage skin cancer model, is not so clear as yet in models used for studies in nutritional carcinogenesis. The animal models for these studies have been primarily rats, mice and hamsters. These have shown that nutrients which appear to have promotion activity are zinc deficiency and 13-cis-retinoic acid for the esophagus; vitamin A deficiency and lipotrope deficiency for the forestomach, unsaturated fat and vitamin A deficiency for liver and colon, lipotrope deficiency for the liver; selenium for the liver. It is probably more correct at this early stage of investigation to consider the effects of nutrients acting either during the time of exposure to the carcinogen, or, after such exposure and when no detectable carcinogen is found in the animals tissues, rather than as promoters in the strict sense. PMID:6873033

  7. New concepts of staging in gastrointestinal tumors as a basis of diagnosis and multimodal therapy.

    PubMed

    Gretschel, S; Moesta, K T; Hünerbein, M; Lange, T; Gebauer, B; Stroszczinski, C; Bembenek, A; Schlag, P M

    2004-02-01

    The therapy of gastrointestinal tumors is becoming more and more sophisticated and complex. This is due to an improved understanding of the pathogenesis of tumors, a more detailed classification and increasing therapeutic options. The basis of optimized therapeutic concepts is the exact evaluation of tumor spread and exact staging. The following review describes some of the most recent staging concepts in gastrointestinal tumors. Multislice computed tomography (CT), positron emission tomography (PET) and new supraparamagnetic iron oxide contrast agents for magnetic resonance imaging enable an increasing quality of the visualization of tumors and metastases. 3D imaging will be used for planning of surgical interventions in the future. Optical coherence tomography may contribute to an improved tumor staging and, thus, to the safety of limited interventions in early oesophageal- and gastric cancer patients. Laparoscopy and laparoscopic ultrasound become increasingly important for the identification of small metastases in the peritoneum, in lymph nodes and in the liver. The sentinel lymph node concept will contribute to an improved staging and individualized therapy as well.

  8. Fluorescent Endoscopy of Tumors in Upper Part of Gastrointestinal Tract

    NASA Astrophysics Data System (ADS)

    Borisova, E.; Vladimirov, B.; Angelov, I.; Avramov, L.

    2007-04-01

    In the recent study delta-aminolevulinic acid/Protoporphyrin IX (5-ALA/PpIX) is used as fluorescent marker for dysplasia and tumor detection in esophagus and stomach. The 5-ALA is administered per os six hours before measurements at dose 20mg/kg weight. High-power light-emitting diode at 405 nm is used as an excitation source. Special opto-mechanical device is built for LED to use the light guide of standard video-endoscopic system (Olimpus Corp.). Through endoscopic instrumental channel a fiber is applied to return information about fluorescence to microspectrometer (USB4000, OceanOptics Inc.). Very good correlation between fluorescence signals and histology examination of the lesions investigated is achieved.

  9. Membrane Glycolipids Content Variety in Gastrointestinal Tumors and Transplantable Hepatomas in Mice

    PubMed Central

    Lv, Jun; Lv, Can Qun; Wang, Bo-Liang; Mei, Ping; Xu, Lei

    2016-01-01

    Background The aim of this study was to investigate the variety of plasma contents of membrane glycolipids in 65 gastrointestinal tumors and 31 transplant hepatomas in mice. Material/Methods The experimental model was a transplantable murine hepatoma. Experimental mice were divided into 3 groups. Results The LSA and TSA content in the 2 groups were significantly difference (p<0.01), and were significantly lower in the therapeutic group than in the control group (p<0.01). Conclusions These results indicate that membrane glycolipids index LSA and TSA are sensitive markers in gastrointestinal tumors. In the transplanted hepatomas in mice, they may be considered as ancillary indicators for judging the therapeutic effect of hepatoma. PMID:27554918

  10. Collection of Biospecimen & Clinical Information in Patients w/ Gastrointestinal Cancers

    ClinicalTrials.gov

    2012-05-24

    Gastrointestinal Neoplasms; Gynecologic Cancers; Gynecologic Cancers Cervical Cancer; Gastric (Stomach) Cancer; Gastro-Esophageal(GE) Junction Cancer; Gastrointenstinal Stromal Tumor (GIST); Colon/Rectal Cancer; Colon/Rectal Cancer Colon Cancer; Colon/Rectal Cancer Rectal Cancer; Colon/Rectal Cancer Anal Cancer; Anal Cancer; Hepatobiliary Cancers; Hepatobiliary Cancers Liver; Pancreatic Cancer

  11. GUIDELINE FOR THE MANAGEMENT OF BILE DUCT CANCERS BY THE BRAZILIAN GASTROINTESTINAL TUMOR GROUP.

    PubMed

    Riechelmann, Rachel; Coutinho, Anelisa K; Weschenfelder, Rui F; Andrade DE Paulo, Gustavo; Fernandes, Gustavo Dos Santos; Gifoni, Markus; Oliveira, Maria de Lourdes; Gansl, Rene; Gil, Roberto; Luersen, Gustavo; Lucas, Lucio; Reisner, Marcio; Vieira, Fernando Meton; Machado, Marcel Autran; Murad, Andre; Osvaldt, Alessandro; Brandão, Miguel; Carvalho, Elisangela; Souza, Tulio; Pfiffer, Tulio; Prolla, Gabriel

    2016-01-01

    The Brazilian Gastrointestinal Tumor Group developed guidelines for the surgical and clinical management of patients with billiary cancers. The multidisciplinary panel was composed of experts in the field of radiology, medical oncology, surgical oncology, radiotherapy, endoscopy and pathology. The panel utilized the most recent literature to develop a series of evidence-based recommendations on different treatment and diagnostic strategies for cholangiocarcinomas and gallbladder cancers.

  12. Expression of dopamine receptors and transporter in neuroendocrine gastrointestinal tumor cells.

    PubMed

    Lemmer, K; Ahnert-Hilger, G; Höpfner, M; Hoegerle, S; Faiss, S; Grabowski, P; Jockers-Scherübl, M; Riecken, E O; Zeitz, M; Scherübl, H

    2002-06-28

    C-11- or F-18-DOPA positron emission tomography (DOPA PET) is a new sensitive imaging technique for small neuroendocrine gastrointestinal tumors which evaluates the decarboxylase activity. To further characterize the dopaminergic system in neuroendocrine gastrointestinal tumor cells, we investigated the expression of both dopamine receptors and the transmembrane dopamine transporter (DAT) in the human neuroendocrine pancreatic cell line BON and in the neuroendocrine gut cell line STC-1. Both BON and STC-1 cells expressed mRNA of the dopamine receptors D2-D5 and DAT. mRNA of the dopamine receptor D1 was detected in BON cells only. Both in BON and STC-1 cells, expression of D2 and D5 receptors and DAT was also demonstrated immunocytochemically. For functional receptor characterization intracellular cAMP levels ([cAMP]i) were determined. Whereas in STC-1 cells dopamine and the D1-like (D1/D5) receptor agonist SKF 38393 increased [cAMP]i, [cAMP]i was decreased by dopamine or the D2-like (D2-D4) receptor agonist quinpirole in BON cells. Functional DAT activity was, however, not detected in either cell line. The presence of both dopamine receptors and of the DAT suggests an autocrine and/or paracrine function of dopamine in neuroendocrine gastrointestinal tumor cells. Yet neither the transmembrane dopamine transporter nor dopamine receptors are likely to contribute to positive DOPA PET imaging of neuroendocrine gastrointestinal tumors. However, these molecules may be of diagnostic importance when applying other dopaminergic system tracers.

  13. Oncogenes and inflammation rewire host energy metabolism in the tumor microenvironment: RAS and NFκB target stromal MCT4.

    PubMed

    Martinez-Outschoorn, Ubaldo E; Curry, Joseph M; Ko, Ying-Hui; Lin, Zhao; Tuluc, Madalina; Cognetti, David; Birbe, Ruth C; Pribitkin, Edmund; Bombonati, Alessandro; Pestell, Richard G; Howell, Anthony; Sotgia, Federica; Lisanti, Michael P

    2013-08-15

    Here, we developed a model system to evaluate the metabolic effects of oncogene(s) on the host microenvironment. A matched set of "normal" and oncogenically transformed epithelial cell lines were co-cultured with human fibroblasts, to determine the "bystander" effects of oncogenes on stromal cells. ROS production and glucose uptake were measured by FACS analysis. In addition, expression of a panel of metabolic protein biomarkers (Caveolin-1, MCT1, and MCT4) was analyzed in parallel. Interestingly, oncogene activation in cancer cells was sufficient to induce the metabolic reprogramming of cancer-associated fibroblasts toward glycolysis, via oxidative stress. Evidence for "metabolic symbiosis" between oxidative cancer cells and glycolytic fibroblasts was provided by MCT1/4 immunostaining. As such, oncogenes drive the establishment of a stromal-epithelial "lactate-shuttle", to fuel the anabolic growth of cancer cells. Similar results were obtained with two divergent oncogenes (RAS and NFκB), indicating that ROS production and inflammation metabolically converge on the tumor stroma, driving glycolysis and upregulation of MCT4. These findings make stromal MCT4 an attractive target for new drug discovery, as MCT4 is a shared endpoint for the metabolic effects of many oncogenic stimuli. Thus, diverse oncogenes stimulate a common metabolic response in the tumor stroma. Conversely, we also show that fibroblasts protect cancer cells against oncogenic stress and senescence by reducing ROS production in tumor cells. Ras-transformed cells were also able to metabolically reprogram normal adjacent epithelia, indicating that cancer cells can use either fibroblasts or epithelial cells as "partners" for metabolic symbiosis. The antioxidant N-acetyl-cysteine (NAC) selectively halted mitochondrial biogenesis in Ras-transformed cells, but not in normal epithelia. NAC also blocked stromal induction of MCT4, indicating that NAC effectively functions as an "MCT4 inhibitor". Taken

  14. RNA Sequencing of Tumor-Associated Microglia Reveals Ccl5 as a Stromal Chemokine Critical for Neurofibromatosis-1 Glioma Growth.

    PubMed

    Solga, Anne C; Pong, Winnie W; Kim, Keun-Young; Cimino, Patrick J; Toonen, Joseph A; Walker, Jason; Wylie, Todd; Magrini, Vincent; Griffith, Malachi; Griffith, Obi L; Ly, Amy; Ellisman, Mark H; Mardis, Elaine R; Gutmann, David H

    2015-10-01

    Solid cancers develop within a supportive microenvironment that promotes tumor formation and growth through the elaboration of mitogens and chemokines. Within these tumors, monocytes (macrophages and microglia) represent rich sources of these stromal factors. Leveraging a genetically engineered mouse model of neurofibromatosis type 1 (NF1) low-grade brain tumor (optic glioma), we have previously demonstrated that microglia are essential for glioma formation and maintenance. To identify potential tumor-associated microglial factors that support glioma growth (gliomagens), we initiated a comprehensive large-scale discovery effort using optimized RNA-sequencing methods focused specifically on glioma-associated microglia. Candidate microglial gliomagens were prioritized to identify potential secreted or membrane-bound proteins, which were next validated by quantitative real-time polymerase chain reaction as well as by RNA fluorescence in situ hybridization following minocycline-mediated microglial inactivation in vivo. Using these selection criteria, chemokine (C-C motif) ligand 5 (Ccl5) was identified as a chemokine highly expressed in genetically engineered Nf1 mouse optic gliomas relative to nonneoplastic optic nerves. As a candidate gliomagen, recombinant Ccl5 increased Nf1-deficient optic nerve astrocyte growth in vitro. Importantly, consistent with its critical role in maintaining tumor growth, treatment with Ccl5 neutralizing antibodies reduced Nf1 mouse optic glioma growth and improved retinal dysfunction in vivo. Collectively, these findings establish Ccl5 as an important microglial growth factor for low-grade glioma maintenance relevant to the development of future stroma-targeted brain tumor therapies.

  15. Fluorescence spectroscopy of gastrointestinal tumors: in vitro studies and in vivo clinical applications

    NASA Astrophysics Data System (ADS)

    Angelova, L.; Borisova, E.; Zhelyazkova, Al.; Keremedchiev, M.; Vladimirov, B.; Avramov, L.

    2013-11-01

    The limitations of standard endoscopy for detection and evaluation of cancerous changes in the gastrointestinal tract (GIT) are significant challenges and initiate development of new diagnostic modalities. Therefore many spectral and optical techniques are applied recently into the clinical practice for obtaining qualitatively and quantitatively new data from gastrointestinal neoplasia with different levels of clinical applicability and diagnostic success. Fluorescence imaging has been one of the most promising technologies in this area. The technique is very topical with its practical application in intra-operative, image-guided resection of tumors, because it permits minimal surgery intervention and friendly therapeutic conditions. The investigations presented here are based on in vitro measurements of excitation-emission matrices (EEM) for GIT neoplasia and in vivo measurements in the frames of initial clinical trial for tumor fluorescence spectra detection, applied for introduction of spectroscopic diagnostic system for optical biopsy of GIT tumors in the daily clinical practice of the University Hospital "Queen Jiovanna - ISUL"- Sofia. Autofluorescence and exogenous fluorescence signals are detected from normal mucosa, inflammation, dysphasia and carcinoma and main spectral features are evaluated. The systems and methods developed for diagnosis and monitoring could open new dimensions in diagnostic and real-time tumor resection. This will make the entire procedure more personal, patient friendly and effective and will help for further understanding of the tumor nature.

  16. A case report of an uncommon sex-cord stromal tumor consisted of luteal and sertoli cells in a spayed bitch.

    PubMed

    Ichimura, Ryohei; Shibutani, Makoto; Mizukami, Sayaka; Suzuki, Terumasa; Shimada, Yuko; Mitsumori, Kunitoshi

    2010-02-01

    We report a rare case of benign sex cord-stromal tumor consisted largely of luteoma with minor portion of Sertoli cell tumor located at the position of the left ovary excision in an 11-year-old ovariectomized bitch. Granulosa cell component was lacking, and both luteal and Sertoli cell portions were entirely positive for inhibin alpha and neuron-specific enolase, whereas luteoma portion alone was positive for Wilms' tumor-1 (WT1), immunohistochemically. The results suggest that this tumor is a possible complication of incomplete ovarian excision at the time of ovariectomy and consisted of uncommon hybrid of luteal and Sertoli cells to be diagnosed as an unclassified sex cord-stromal tumor if applied in human cases. WT1-expression pattern suggested the signature of the difference in the phenotype of these cell types.

  17. Laparoscopic resection of gastrointestinal neuroendocrine tumors with special contribution of radionuclide imaging

    PubMed Central

    Shamiyeh, Andreas; Gabriel, Michael

    2014-01-01

    The surgical treatment of neuroendocrine tumors (NETs) draws on experience and guidelines more than on prospective randomized trials. The incidence of NET is increasing in all parts of the gastrointestinal tract. A variety of classifications introduced over the last decade may have led to difficulties in judging clinical relevance and determining the right surgical strategy. The North American Neuroendocrine Tumor Society and the European Neuroendocrine Tumor Society have developed usable guidelines from the available literature. For more than 20 years laparoscopy has developed as the gold standard for various surgical indications. Nevertheless, few trials have compared open and laparoscopic surgery with regard to NET. This review summarizes the recent literature on surgery for NET and incorporates the evidence on laparoscopy for cancer which might be also applied for NET. PMID:25400444

  18. Identification of Sonic Hedgehog-Induced Stromal Factors That Stimulate Prostate Tumor Growth

    DTIC Science & Technology

    2007-11-01

    features of the mesenchymal-epithelial interactions of development may play a critical role in the development of benign prostatic hyperplasia and in the...proceeds (Hayward et al., 1996). Myofibroblasts are present in the adult prostate at sites of benign prostatic hyperplasia (BPH) and in prostate...Wang, S.Y., Vazquez, D.V., C, C.X., Zhang, S., and Tang, L. (2007) Prostatic stromal cells derived from benign prostatic hyperplasia specimens possess

  19. A Case Report: Pseudoangiomatous Stromal Hyperplasia Tumor Presenting as a Palpable Mass

    PubMed Central

    Vo, Q. D.; Koch, G.; Girard, J. M.; Zamora, L.; Bouquet de Jolinière, Jean; Khomsi, F.; Feki, A.; Hoogewoud, H. M.

    2016-01-01

    We report a case of woman with a palpable lump on her left breast. On mammography, a huge mass located between the inner and the outer inferior breast quadrants of the left breast was found. The ultrasound examination realized later revealed a heterogeneous mass with smooth and lobulated borders. An MRI was also performed, showing an oval mass with heterogeneous areas of enhancement. Finally, a core biopsy under sonographic guidance revealed a pseudoangiomatous stromal hyperplasia of the breast. PMID:26835457

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

    DTIC Science & Technology

    2010-04-01

    ADAM family members in cancer. ADAM12 is expressed in carcinoma and promotes breast cancer progression by inducing the apoptosis of surrounding...stromal cells (13). Consequently, ADAM12 protein levels correlate with advanced breast cancer (14, 15). In contrast, the disintegrin domain of ADAM15...subgroup of ADAMs that also contains ADAM12 and ADAM15 (18). The ADAM9 metalloprotease activity cleaves heparin-binding epidermal growth factor (HB

  1. A fibromyxoid stromal response is associated with an infiltrative tumor morphology, perineural invasion, and lymph node metastasis in squamous cell carcinoma of the vulva.

    PubMed

    Jeffus, Susanne K; Gehlot, Ashita; Holthoff, Emily; Stone, Rebecca; Spencer, Horace; Kelly, Thomas; Post, Steven R; Quick, Charles M

    2015-09-01

    Patterns of invasion and stromal response are understudied in vulvar squamous cell carcinoma. The aim of this study was to explore whether histologic features such as an infiltrative pattern of invasion and fibromyxoid stromal response (FMX-SR) are meaningful prognostic factors. We reviewed 143 vulvar squamous cell carcinoma resections and correlated patterns of invasion and stromal response with patient age, ethnicity, depth of invasion, tumor size, perineural invasion (S100/AE1/3 stain), lymph node involvement (LNI), extranodal extension, margin status, pathologic stage, and recurrence. Univariate analyses of continuous variables were performed using t tests, whereas Pearson χ tests were used for categorical variables. Logistic regression analyses examined the relationship between histopathologic characteristics and clinical outcomes. There was a statistically significant association between infiltrative tumors and an FMX-SR in comparison with noninfiltrative tumors (P<0.001). Tumors with FMX-SR were significantly more deeply invasive (P=0.0025) and more likely to have LNI (P=0.0364), extranodal extension (P=0.0227), and perineural invasion (P=0.0011) compared with tumors without FMX-SR. For cases with negative surgical margins, the association between tumors with FMX-SR and LNI was significantly strengthened (odds ratio=4.73, P=0.0042), even after adjustments for age, race, and depth of invasion (odds ratio=4.34, P=0.0154). The presence of both FMX-SR and an infiltrative pattern of invasion in tumors with negative margins was significantly associated with LNI (P=0.0235) and recurrence (P=0.0124). These results suggest that interactions between nerve, tumor, and stromal cells play a role in tumor progression and represent additional prognostic factors that help stratify those patients at highest risk for LNI, extranodal extension, and recurrence.

  2. Aminobisphosphonates prevent the inhibitory effects exerted by lymph node stromal cells on anti-tumor Vδ 2 T lymphocytes in non-Hodgkin lymphomas.

    PubMed

    Musso, Alessandra; Catellani, Silvia; Canevali, Paolo; Tavella, Sara; Venè, Roberta; Boero, Silvia; Pierri, Ivana; Gobbi, Marco; Kunkl, Annalisa; Ravetti, Jean-Louis; Zocchi, Maria Raffaella; Poggi, Alessandro

    2014-01-01

    In this study, we analyzed the influence of mesenchymal stromal cells derived from lymph nodes of non-Hodgkin's lymphomas, on effector functions and differentiation of Vdelta (δ)2 T lymphocytes. We show that: i) lymph-node mesenchymal stromal cells of non-Hodgkin's lymphoma inhibit NKG2D-mediated lymphoid cell killing, but not rituximab-induced antibody-dependent cell-mediated cytotoxicity, exerted by Vδ2 T lymphocytes; ii) pre-treatment of mesenchymal stromal cells with the aminobisphosphonates pamidronate or zoledronate can rescue lymphoma cell killing via NKG2D; iii) this is due to inhibition of transforming growth factor-β and increase in interleukin-15 production by mesenchymal stromal cells; iv) aminobisphosphonate-treated mesenchymal stromal cells drive Vδ2 T-lymphocyte differentiation into effector memory T cells, expressing the Thelper1 cytokines tumor necrosis factor-α and interferon-γ. In non-Hodgkin's lymphoma lymph nodes, Vδ2 T cells were mostly naïve; upon co-culture with autologous lymph-node mesenchymal stromal cells exposed to zoledronate, the percentage of terminal differentiated effector memory Vδ2 T lymphocytes increased. In all non-Hodgkin's lymphomas, low or undetectable transcription of Thelper1 cytokines was found. In diffused large B-cell lymphomas and in a group of follicular lymphoma, transcription of transforming growth factor β and interleukin-10 was enhanced compared to non-neoplastic lymph nodes. Thus, in non-Hodgkin lymphomas mesenchymal stromal cells interfere with Vδ2 T-lymphocyte cytolytic function and differentiation to Thelper1 and/or effector memory cells, depending on the prominent in situ cytokine milieu. Aminobisphosphonates, acting on lymph-node mesenchymal stromal cells, can push the balance towards Thelper1/effector memory and rescue the recognition and killing of lymphoma cells through NKG2D, sparing rituximab-induced antibody-dependent cell-mediated cytotoxicity.

  3. Kit K641E oncogene up-regulates Sprouty homolog 4 and Trophoblast glycoprotein in interstitial cells of Cajal in a murine model of gastrointestinal stromal tumours

    PubMed Central

    Gromova, Petra; Ralea, Sebastian; Lefort, Anne; Libert, Frédérick; Rubin, Brian P; Erneux, Christophe; Vanderwinden, Jean-Marie

    2009-01-01

    Gastrointestinal stromal tumours (GIST) are thought to derive from the interstitial cells of Cajal (ICC) or an ICC precursor. Oncogenic mutations of the receptor tyrosine kinase KIT are present in most GIST. KIT K642E was originally identified in sporadic GIST and later found in the germ line of a familial GIST cohort. A mouse model harbouring a germline Kit K641E mutant was created to model familial GIST. The expression profile was investigated in the gastric antrum of the KitK641E murine GIST model by microarray, quantitative PCR and immunofluorescence. Gja1/Cx43, Gpc6, Gpr133, Pacrg, Pde3a, Prkar2b, Prkcq/Pkce, Rasd2, Spry4 and Tpbg/5T4 were found to be up-regulated. The proteins encoded by Gja1/Cx43, Pde3a, Prkcq/Pkce were localized in Kit-ir ICC in wild-type and KitK641E animals while Spry4 and Tpbg/5T4 were detected in Kit-ir cells only in KitK641E, but not in KitWT/WT animals. Most up-regulated genes in this mouse model belong to the gene expression profile of human GIST but also to the profile of normal Kit+ ICC in the mouse small intestine. Spry4 and Tpbg/5T4 may represent candidates for targeted therapeutic approaches in GIST with oncogenic KIT mutations. PMID:19453770

  4. Effective Downsizing of a Large Oesophageal Gastrointestinal Stromal Tumour with Neoadjuvant Imatinib Enabling an Uncomplicated and without Tumour Rupture Laparoscopic-Assisted Ivor-Lewis Oesophagectomy

    PubMed Central

    Costa Neves, Mafalda; Giakoustidis, Alexandros; Benson, Charlotte

    2015-01-01

    Neoadjuvant imatinib for gastrointestinal stromal tumours (GISTs) is increasingly used nowadays. As oesophagectomy is associated with high morbidity and mortality, a preoperative downsizing of an oesophageal GIST to limit the extent of resection would be ideal. Because these tumours are rare and neoadjuvant treatment with imatinib is recent, there is limited literature available regarding neoadjuvant administration of imatinib in patients with oesophageal GISTs. A 50-year-old woman presented with total dysphagia. An upper endoscopy and biopsy revealed a large submucosal KIT-positive GIST obstructing the mid oesophagus. CT confirmed a lesion measuring 99 mm × 50 mm × 104 mm. Because the size and location of the tumour increased the risk of intraoperative rupture, it was decided to administer preoperative imatinib. The patient had an excellent clinical and radiological response. Her dysphagia gradually resolved and the follow-up CT scans of the first 10 months showed a gradually reducing tumour size to 54 mm × 33 mm × 42 mm. The patient underwent an uneventful laparoscopic-assisted Ivor-Lewis oesophagectomy. Postoperatively, the patient continued with adjuvant imatinib. At the last follow-up, 1 year from operation and 38 months from the diagnosis, the patient is disease free. PMID:26075122

  5. Consensus report on the radiological management of patients with gastrointestinal stromal tumours (GIST): recommendations of the German GIST Imaging Working Group.

    PubMed

    Kalkmann, Janine; Zeile, Martin; Antoch, Gerald; Berger, Frank; Diederich, Stefan; Dinter, Dietmar; Fink, Christian; Janka, Rolf; Stattaus, Jörg

    2012-05-07

    The aim was to reach consensus in imaging for staging and follow-up as well as for therapy response assessment in patients with gastrointestinal stromal tumours (GIST). The German GIST Imaging Working Group was formed by 9 radiologists engaged in assessing patients with GIST treated with targeted therapy. The following topics were discussed: indication and optimal acquisition techniques of computed tomography (CT), magnetic resonance imaging (MRI) and positron emission tomography (PET)/CT; tumour response assessment considering response criteria and measurement techniques on CT, MRI and PET/CT; result interpretation; staging interval and pitfalls. Contrast-enhanced CT is the standard method for GIST imaging. MRI is the method of choice in case of liver-specific questions or contraindications to CT. PET/CT should be used for early response assessment or inconclusive results on morphologic imaging. All imaging techniques should be standardized allowing a reliable response assessment. Response has to be assessed with respect to lesion size, lesion density and appearance of new lesions. A critical issue is pseudoprogression due to myxoid degeneration or intratumoural haemorrhage. The management of patients with GIST receiving a targeted therapy requires a standardized algorithm for imaging and an appropriate response assessment with respect to changes in lesion size and density.

  6. Effective Downsizing of a Large Oesophageal Gastrointestinal Stromal Tumour with Neoadjuvant Imatinib Enabling an Uncomplicated and without Tumour Rupture Laparoscopic-Assisted Ivor-Lewis Oesophagectomy.

    PubMed

    Neofytou, Kyriakos; Costa Neves, Mafalda; Giakoustidis, Alexandros; Benson, Charlotte; Mudan, Satvinder

    2015-01-01

    Neoadjuvant imatinib for gastrointestinal stromal tumours (GISTs) is increasingly used nowadays. As oesophagectomy is associated with high morbidity and mortality, a preoperative downsizing of an oesophageal GIST to limit the extent of resection would be ideal. Because these tumours are rare and neoadjuvant treatment with imatinib is recent, there is limited literature available regarding neoadjuvant administration of imatinib in patients with oesophageal GISTs. A 50-year-old woman presented with total dysphagia. An upper endoscopy and biopsy revealed a large submucosal KIT-positive GIST obstructing the mid oesophagus. CT confirmed a lesion measuring 99 mm × 50 mm × 104 mm. Because the size and location of the tumour increased the risk of intraoperative rupture, it was decided to administer preoperative imatinib. The patient had an excellent clinical and radiological response. Her dysphagia gradually resolved and the follow-up CT scans of the first 10 months showed a gradually reducing tumour size to 54 mm × 33 mm × 42 mm. The patient underwent an uneventful laparoscopic-assisted Ivor-Lewis oesophagectomy. Postoperatively, the patient continued with adjuvant imatinib. At the last follow-up, 1 year from operation and 38 months from the diagnosis, the patient is disease free.

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

    PubMed

    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.

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

    PubMed

    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.

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

    PubMed

    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.

  10. [Severe lower gastrointestinal bleeding due to GIST tumor. Radiological embolization and surgery].

    PubMed

    Navas, Diana; Ríos, Antonio; Febrero, Beatriz; Rodríguez, José Manuel; Lloret, Francisco; Parrilla, Pascual

    2014-01-01

    Antecedentes: los tumores del estroma gastrointestinal (GIST) se identificaron hace muy poco tiempo. Son tumores que no suelen alertar con síntomas mientras permanecen en fase localizada, operable y curable. Aunque son poco frecuentes, cuando no se diagnostican y tratan oportunamente son muy agresivos. Su manifestación clínica más común es la hemorragia gastrointestinal por erosión de la mucosa, pero su presentación como hemorragia baja del tubo digestivo severa es excepcional. Caso clínico: se comunica un caso de hemorragia baja del tubo digestivo severa estabilizada por radiología intervencionista, que posteriormente requirió cirugía para su tratamiento definitivo. Conclusiones: la embolización radiológica está cada vez más difundida como tratamiento de hemorragias en distintos sitios porque permite la estabilización hemodinámica de los pacientes. No hay que olvidar, sin embargo, que en los casos de hemorragia baja del tubo digestivo, de origen desconocido, es necesario investigar las posibles causas.

  11. NOTCH receptors in gastric and other gastrointestinal cancers: oncogenes or tumor suppressors?

    PubMed

    Huang, Tingting; Zhou, Yuhang; Cheng, Alfred S L; Yu, Jun; To, Ka Fai; Kang, Wei

    2016-12-09

    Gastric cancer (GC) ranks the most common cancer types and is one of the leading causes of cancer-related death. Due to delayed diagnosis and high metastatic frequency, 5-year survival rate of GC is rather low. It is a complex disease resulting from the interaction between environmental factors and host genetic alterations that deregulate multiple signaling pathways. The Notch signaling pathway, a highly conserved system in the regulation of the fate in several cell types, plays a pivotal role in cell differentiation, survival and proliferation. Notch is also one of the most commonly activated signaling pathways in tumors and its aberrant activation plays a key role in cancer advancement. Whether Notch cascade exerts oncogenic or tumor suppressive function in different cancer types depends on the cellular context. Mammals have four NOTCH receptors that modulate Notch pathway activity. In this review, we provide a comprehensive summary on the functional role of NOTCH receptors in gastric and other gastrointestinal cancers. Increasing knowledge of NOTCH receptors in gastrointestinal cancers will help us recognize the underlying mechanisms of Notch signaling and develop novel therapeutic strategies for GC.

  12. MAOA-Dependent Activation of Shh-IL6-RANKL Signaling Network Promotes Prostate Cancer Metastasis by Engaging Tumor-Stromal Cell Interactions.

    PubMed

    Wu, Jason Boyang; Yin, Lijuan; Shi, Changhong; Li, Qinlong; Duan, Peng; Huang, Jen-Ming; Liu, Chunyan; Wang, Fubo; Lewis, Michael; Wang, Yang; Lin, Tzu-Ping; Pan, Chin-Chen; Posadas, Edwin M; Zhau, Haiyen E; Chung, Leland W K

    2017-03-13

    Metastasis is a predominant cause of death for prostate cancer (PCa) patients; however, the underlying mechanisms are poorly understood. We report that monoamine oxidase A (MAOA) is a clinically and functionally important mediator of PCa bone and visceral metastases, activating paracrine Shh signaling in tumor-stromal interactions. MAOA provides tumor cell growth advantages in the bone microenvironment by stimulating interleukin-6 (IL6) release from osteoblasts, and triggers skeletal colonization by activating osteoclastogenesis through osteoblast production of RANKL and IL6. MAOA inhibitor treatment effectively reduces metastasis and prolongs mouse survival by disengaging the Shh-IL6-RANKL signaling network in stromal cells in the tumor microenvironment. These findings provide a rationale for targeting MAOA and its associated molecules to treat PCa metastasis.

  13. Endometriosis-associated serous borderline tumor and endometrial stromal sarcoma of the ovary: a report of a rare lesion in an infant.

    PubMed

    Ho, Ronnie S L; Chan, Godfrey C F; Ha, Shau Yin; Ip, Philip P C

    2012-01-01

    Endometriosis in infancy is most unusual, and associated tumors in this age group are exceptionally rare. We report a case of a serous borderline tumor and endometrial stromal sarcoma arising in an ovarian endometriotic cyst. The patient was an infant of 18 months of age who presented with an incidental abdominal mass. The serum sex hormones were at prepubertal levels. There was no evidence of precocious puberty or any obvious genital anomaly. Intraoperative findings included a solitary solid and multicystic right ovarian mass without evidence of any extraovarian disease. On microscopic examination, the tumor was composed of an intimate mixture of florid papillary and stromal cell proliferation in the wall of an endometriotic cyst. The papillae showed hierarchical branching and had hyalinized and edematous cores with scattered psammoma bodies. The epithelial cells were mildly atypical and mitotically inactive. The underlying endometrial stromal cells were arranged in irregular tongues that permeated the thickened fibrous cyst wall. They were mitotically active and immunoreactive for CD10. There was no evidence of any primitive germ cell tumor. The patient received no adjuvant treatment and had an uneventful postoperative follow-up period of 30 months. To the best of our knowledge, endometriosis associated with this most unusual combination of ovarian tumors has never been reported in an infant.

  14. Efficacy of CAR T-cell therapy in large tumors relies upon stromal targeting by IFNγ.

    PubMed

    Textor, Ana; Listopad, Joanna J; Wührmann, Lara Le; Perez, Cynthia; Kruschinski, Anna; Chmielewski, Markus; Abken, Hinrich; Blankenstein, Thomas; Charo, Jehad

    2014-12-01

    Adoptive T-cell therapy using chimeric antigen receptor-modified T cells (CAR-T therapy) has shown dramatic efficacy in patients with circulating lymphoma. However, eradication of solid tumors with CAR-T therapy has not been reported yet to be efficacious. In solid tumors, stroma destruction, due to MHC-restricted cross-presentation of tumor antigens to T cells, may be essential. However, CAR-Ts recognize antigens in an MHC-independent manner on cancer cells but not stroma cells. In this report, we show how CAR-Ts can be engineered to eradicate large established tumors with provision of a suitable CD28 costimulatory signal. In an HER2-dependent tumor model, tumor rejection by HER2-specific CAR-Ts was associated with sustained influx and proliferation of the adoptively transferred T cells. Interestingly, tumor rejection did not involve natural killer cells but was associated instead with a marked increase in the level of M1 macrophages and a requirement for IFNγ receptor expression on tumor stroma cells. Our results argue that CAR-T therapy is capable of eradicating solid tumors through a combination of antigen-independent stroma destruction and antigen-specific tumor cell targeting.

  15. Intraoperative localization of early-stage gastrointestinal tumors using a marking clip detector system.

    PubMed

    Ohdaira, Takeshi; Nagai, Hideo; Shibusawa, Hiroyuki

    2005-01-01

    Intraoperative Tumor site recognition is extremely difficult during laparoscopic surgical treatment of early-stage gastrointestinal carcinoma. A novel marking method that uses both metallic clips and a marking clip detector system (MCDS, Olympus Optical Co., Tokyo, Japan) modified from a metal detector system, was designed by the authors. Metallic clips were applied to the tumor site during preoperative endoscopy, and the clip site was identified intraoperatively using the MCDS. In a basic ex vivo study, three metallic clips were detected easily (100% detection). In a clinical study, the marking site was detected in all gastric cancer patients who underwent laparoscopic subtotal gastrectomy. The mean distance between detected site and clip along the longitudinal bowel axis was 6.4 +/- 2.9 mm. Mean detection time was 18.1 +/- 5.7 seconds. None of the patients in this study experienced complications from this marking technique. MCDS allows accurate identification of tumor sites. This method may be useful for tumor-site identification during laparoscopic gastrectomy.

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

    DTIC Science & Technology

    2015-10-01

    Tables 1‐3, Appendix 3), we generated a correlation network of  gene  modules (Figure 6, Appendix 2).   This  correlation  map   revealed  two main...and stromal  gene  modules combined  with  an  evaluation  of  their  correlation  allowed  us  to  generate  a module  interaction  map   (Figure  6,  8...generated an interaction/correlation  map  of these  gene  modules.   These are critical steps towards  accomplishing  our major  objectives  and

  17. A pharmaco-economic analysis of second-line treatment with imatinib or sunitinib in patients with advanced gastrointestinal stromal tumours

    PubMed Central

    Contreras-Hernández, I; Mould-Quevedo, J F; Silva, A; Salinas-Escudero, G; Villasís-Keever, M A; Granados-García, V; Dávila-Loaiza, G; Petersen, J A; Garduño-Espinosa, J

    2008-01-01

    Second-line treatments recommended by the National Cancer Center Network to manage advanced-stage gastrointestinal stromal tumours (GIST) were evaluated to determine the cost and cost-effectiveness of each intervention in the Mexican insurance system, the Instituto Mexicano del Seguro Social (IMSS). Treatments examined over a 5-year temporal horizon to estimate long-term costs included 800 mg day−1 of imatinib mesylate, 50 mg day−1 of sunitinib malate (administered in a 4 week on/2 week rest schedule), and palliative care. The mean cost (MC), cost-effectiveness, and benefit of each intervention were compared to determine the best GIST treatment from the institutional perspective of the IMSS. As sunitinib was not reimbursed at the time of the study, a Markov model and sensitivity analysis were conducted to predict the MC and likelihood of reimbursement. Patients taking 800 mg day−1 of imatinib had the highest MC (±s.d.) of treatment at $35 225.61 USD (±1253.65 USD); while sunitinib incurred a median MC of $17 805.87 USD (±694.83 USD); and palliative care had the least MC over treatment duration as the cost was $2071.86 USD (±472.88 USD). In comparison to palliative care, sunitinib is cost-effective for 38.9% of patients; however, sunitinib delivered the greatest survival benefit as 5.64 progression-free months (PFM) and 1.4 life-years gained (LYG) were obtained in the economic model. Conversely, patients on imatinib and palliative care saw a lower PFM of 5.28 months and 2.58 months and also fewer LYG (only 1.31 and 1.08 years, respectively). Therefore, economic modeling predicts that reimbursing sunitinib over high dose imatinib in the second-line GIST indication would deliver cost savings to the IMSS and greater survival benefits to patients. PMID:18506179

  18. A pharmaco-economic analysis of second-line treatment with imatinib or sunitinib in patients with advanced gastrointestinal stromal tumours.

    PubMed

    Contreras-Hernández, I; Mould-Quevedo, J F; Silva, A; Salinas-Escudero, G; Villasís-Keever, M A; Granados-García, V; Dávila-Loaiza, G; Petersen, J A; Garduño-Espinosa, J

    2008-06-03

    Second-line treatments recommended by the National Cancer Center Network to manage advanced-stage gastrointestinal stromal tumours (GIST) were evaluated to determine the cost and cost-effectiveness of each intervention in the Mexican insurance system, the Instituto Mexicano del Seguro Social (IMSS). Treatments examined over a 5-year temporal horizon to estimate long-term costs included 800 mg day(-1) of imatinib mesylate, 50 mg day(-1) of sunitinib malate (administered in a 4 week on/2 week rest schedule), and palliative care. The mean cost (MC), cost-effectiveness, and benefit of each intervention were compared to determine the best GIST treatment from the institutional perspective of the IMSS. As sunitinib was not reimbursed at the time of the study, a Markov model and sensitivity analysis were conducted to predict the MC and likelihood of reimbursement. Patients taking 800 mg day(-1) of imatinib had the highest MC (+/-s.d.) of treatment at $35,225.61 USD (+/-1253.65 USD); while sunitinib incurred a median MC of $17,805.87 USD (+/-694.83 USD); and palliative care had the least MC over treatment duration as the cost was $2071.86 USD (+/-472.88 USD). In comparison to palliative care, sunitinib is cost-effective for 38.9% of patients; however, sunitinib delivered the greatest survival benefit as 5.64 progression-free months (PFM) and 1.4 life-years gained (LYG) were obtained in the economic model. Conversely, patients on imatinib and palliative care saw a lower PFM of 5.28 months and 2.58 months and also fewer LYG (only 1.31 and 1.08 years, respectively). Therefore, economic modeling predicts that reimbursing sunitinib over high dose imatinib in the second-line GIST indication would deliver cost savings to the IMSS and greater survival benefits to patients.

  19. miRNA-221 and miRNA-222 induce apoptosis via the KIT/AKT signalling pathway in gastrointestinal stromal tumours.

    PubMed

    Ihle, Michaela Angelika; Trautmann, Marcel; Kuenstlinger, Helen; Huss, Sebastian; Heydt, Carina; Fassunke, Jana; Wardelmann, Eva; Bauer, Sebastian; Schildhaus, Hans-Ulrich; Buettner, Reinhard; Merkelbach-Bruse, Sabine

    2015-08-01

    Aberrantly expressed microRNAs (miRNAs) are involved in many diseases including cancer. In gastrointestinal stromal tumours (GISTs) expression of miR-221 and miR-222 is reduced compared to control tissue and other sarcomas but the functional effects of this downregulation are not fully understood. This study aimed at evaluating the miR-221 and miR-222 expression profiles in different GIST subtypes and the functional role of these miRNAs. Expression of miR-221 and miR-222 was analysed in six KIT exon 9 and three KIT exon 11 mutated and nine wildtype GISTs by qPCR. Viability and apoptosis were examined in three different, KIT positive GIST cell lines (GIST882, GIST-T1 and GIST48) after overexpression of these miRNAs. The modulation of KIT and the PI3K/AKT pathways was determined by Western blot. Wildtype and KIT mutated GISTs revealed reduced miRNA expression compared to adequate control tissue. miRNA expression was lower for wildtype compared to mutated GISTs. Transient transfection of miR-221 and miR-222 reduced viability and induced apoptosis by inhibition of KIT expression and its phosphorylation and activation of caspases 3 and 7 in all three GIST cell lines. p-AKT, AKT and BCL2 expression was reduced after miRNA transfection whereas only slight influence on p-MTOR, MTOR and BCL2L11 (BIM) was detected. Our results demonstrate that miR-221 and miR-222 which are downregulated in wildtype and mutated GISTs, induce apoptosis in vitro by a signalling cascade involving KIT, AKT and BCL2. Therefore, overexpression of these miRNAs seems to functionally counteract oncogenic signalling pathways in GIST.

  20. Advanced Imaging Approaches to Characterize Stromal and Metabolic Changes in In Vivo Mammary Tumor Models

    DTIC Science & Technology

    2015-02-01

    Optical imaging , metabolism, tumor microenvironment, NADH, FAD, intravital imaging , collagen, metastasis 3.Overall Project Summary Our preliminary...Keely, KW Eliceiri. Novel Intravital Imaging Approaches to Characterize Collagen Alignment in Defined Mammary Tumor Models. Microscopy and...fixturing for intravital FLIM imaging through a rodent mammary imaging window. Stage is raised to accommodate tall 20xW objective. 14     Figure

  1. Bone morphogenetic protein antagonist gremlin 1 is widely expressed by cancer-associated stromal cells and can promote tumor cell proliferation

    NASA Astrophysics Data System (ADS)

    Sneddon, Julie B.; Zhen, Hanson H.; Montgomery, Kelli; van de Rijn, Matt; Tward, Aaron D.; West, Robert; Gladstone, Hayes; Chang, Howard Y.; Morganroth, Greg S.; Oro, Anthony E.; Brown, Patrick O.

    2006-10-01

    Although tissue microenvironments play critical roles in epithelial development and tumorigenesis, the factors mediating these effects are poorly understood. In this work, we used a genomic approach to identify factors produced by cells in the microenvironment of basal cell carcinoma (BCC) of the skin, one of the most common human cancers. The global gene expression programs of stromal cell cultures derived from human BCCs showed consistent, systematic differences from those derived from nontumor skin. The gene most consistently expressed at a higher level in BCC tumor stromal cells compared with those from nontumor skin was GREMLIN 1, which encodes a secreted antagonist of the bone morphogenetic protein (BMP) pathway. BMPs and their antagonists are known to play a crucial role in stem and progenitor cell biology as regulators of the balance between expansion and differentiation. Consistent with the hypothesis that BMP antagonists might have a similar role in cancer, we found GREMLIN 1 expression in the stroma of human BCC tumors but not in normal skin in vivo. Furthermore, BMP 2 and 4 are expressed by BCC cells. Ex vivo, BMP inhibits, and Gremlin 1 promotes, proliferation of cultured BCC cells. We further found that GREMLIN 1 is expressed by stromal cells in many carcinomas but not in the corresponding normal tissue counterparts that we examined. Our data suggest that BMP antagonists may be important constituents of tumor stroma, providing a favorable microenvironment for cancer cell survival and expansion in many cancers. cancer biology | stem cell regulation | tissue microenvironment | tumor stroma

  2. Tumor-associated Endo180 requires stromal-derived LOX to promote metastatic prostate cancer cell migration on human ECM surfaces.

    PubMed

    Caley, Matthew P; King, Helen; Shah, Neel; Wang, Kai; Rodriguez-Teja, Mercedes; Gronau, Julian H; Waxman, Jonathan; Sturge, Justin

    2016-02-01

    The diverse composition and structure of extracellular matrix (ECM) interfaces encountered by tumor cells at secondary tissue sites can influence metastatic progression. Extensive in vitro and in vivo data has confirmed that metastasizing tumor cells can adopt different migratory modes in response to their microenvironment. Here we present a model that uses human stromal cell-derived matrices to demonstrate that plasticity in tumor cell movement is controlled by the tumor-associated collagen receptor Endo180 (CD280, CLEC13E, KIAA0709, MRC2, TEM9, uPARAP) and the crosslinking of collagen fibers by stromal-derived lysyl oxidase (LOX). Human osteoblast-derived and fibroblast-derived ECM supported a rounded 'amoeboid-like' mode of cell migration and enhanced Endo180 expression in three prostate cancer cell lines (PC3, VCaP, DU145). Genetic silencing of Endo180 reverted PC3 cells from their rounded mode of migration towards a bipolar 'mesenchymal-like' mode of migration and blocked their translocation on human fibroblast-derived and osteoblast-derived matrices. The concomitant decrease in PC3 cell migration and increase in Endo180 expression induced by stromal LOX inhibition indicates that the Endo180-dependent rounded mode of prostate cancer cell migration requires ECM crosslinking. In conclusion, this study introduces a realistic in vitro model for the study of metastatic prostate cancer cell plasticity and pinpoints the cooperation between tumor-associated Endo180 and the stiff microenvironment imposed by stromal-derived LOX as a potential target for limiting metastatic progression in prostate cancer.

  3. Overcoming the stromal barrier for targeted delivery of HPMA copolymers to pancreatic tumors.

    PubMed

    Buckway, Brandon; Wang, Yongjian; Ray, Abhijit; Ghandehari, Hamidreza

    2013-11-01

    Delivery of macromolecules to pancreatic cancer is inhibited by a dense extracellular matrix composed of hyaluronic acid, smooth muscle actin and collagen fibers. Hyaluronic acid causes a high intratumoral fluidic pressure which prevents diffusion and penetration into the pancreatic tumor. This study involves the breaking down of hyaluronic acid by treating CAPAN-1 xenograft tumors in athymic nu/nu mice with targeted N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers radiolabeled with (111)In for single photon emission computerized tomography (SPECT) imaging. Two targeting strategies were investigated including αvβ3 integrin and HER2 receptors. HPMA copolymers were targeted to these receptors by conjugating short peptide ligands cRGDfK and KCCYSL to the side chains of the copolymer. Results demonstrate that tumor targeting can be achieved in vivo after treatment with hyaluronidase. This approach shows promise for enhanced delivery of polymer-peptide conjugates to solid tumors.

  4. Optical imaging of breast tumors and of gastrointestinal cancer by laser-induced fluorescence.

    PubMed

    Ebert, Bernd; Grosenick, Dirk

    2013-01-01

    Optical imaging offers a high potential for noninvasive detection of cancer in humans. Recent advances in instrumentation for diffuse optical imaging have led to new capabilities for the detection of cancer in highly scattering tissue such as the female breast. We review recent developments in the detection of breast cancer in humans by fluorescent contrast agents. So far, the unspecific contrast agents indocyanine green (ICG) and omocyanine have been applied, whereas molecular probes for direct targeted imaging of this disease are still in preclinical research. We discuss recent improvements in the differentiation of malignant and benign lesions with ICG based on its enhanced extravasation in breast cancer. Whereas fluorescence imaging in thick tissue layers is hampered by strong light scattering, tissue surfaces can be investigated with high spatial resolution. As an example for superficial tumors, lesions of the gastrointestinal tract (GI) are discussed. In these investigations, protoporphyrin IX is used as a tumor-specific (due to its strong enhancement in tumor cells) target for spectroscopic identification and imaging. We present a time-gated method for fluorescence imaging and spectroscopy with strong suppression of tissue autofluorescence and show results on patients with Barrett's esophagus and with colitis ulcerosa.

  5. A 3D in vitro model of patient-derived prostate cancer xenograft for controlled interrogation of in vivo tumor-stromal interactions.

    PubMed

    Fong, Eliza L S; Wan, Xinhai; Yang, Jun; Morgado, Micaela; Mikos, Antonios G; Harrington, Daniel A; Navone, Nora M; Farach-Carson, Mary C

    2016-01-01

    Patient-derived xenograft (PDX) models better represent human cancer than traditional cell lines. However, the complex in vivo environment makes it challenging to employ PDX models to investigate tumor-stromal interactions, such as those that mediate prostate cancer (PCa) bone metastasis. Thus, we engineered a defined three-dimensional (3D) hydrogel system capable of supporting the co-culture of PCa PDX cells and osteoblastic cells to recapitulate the PCa-osteoblast unit within the bone metastatic microenvironment in vitro. Our 3D model not only maintained cell viability but also preserved the typical osteogenic phenotype of PCa PDX cells. Additionally, co-culture cellularity was maintained over that of either cell type cultured alone, suggesting that the PCa-osteoblast cross-talk supports PCa progression in bone, as is hypothesized to occur in patients with prostatic bone metastasis. Strikingly, osteoblastic cells co-cultured with PCa PDX tumoroids organized around the tumoroids, closely mimicking the architecture of PCa metastases in bone. Finally, tumor-stromal signaling mediated by the fibroblast growth factor axis tightly paralleled that in the in vivo counterpart. Together, these findings indicate that this 3D PCa PDX model recapitulates important pathological properties of PCa bone metastasis, and validate the use of this model for controlled and systematic interrogation of complex in vivo tumor-stromal interactions.

  6. Stromal Overgrowth in a Brenner Tumor or Ovarian Fibroma With Minor Sex Cord Elements?

    PubMed

    Ross, Julia A; Saglam, Ozlen

    2015-07-01

    Computed tomography obtained as part of a urinary tract assessment in a 68-year-old woman incidentally detected a solid adnexal mass. Bilateral salpingo-oophorectomy revealed a unilateral, 4-cm, white to tan-yellow colored, focally calcified, left ovarian mass. Microscopically, the tumor was composed of bland fibroblasts, abundant collagen, and areas of calcification with a minor component composed of nests of epithelial cells with nuclear clefts focally evident, some of which contained central lumens with eosinophilic secretions. The major considerations were fibromatous overgrowth in a Brenner tumor or ovarian fibroma with minor sex cord elements. Immunostains for cytokeratin 7 showed diffuse positivity in the epithelial nests, whereas cytokeratin 20 and inhibin were negative, further supporting the diagnosis of a Brenner tumor.

  7. Biphasic malignant testicular sex cord-stromal tumor in a cotton-top tamarin (Saguinus oedipus) with review of the literature.

    PubMed

    Yearley, J H; King, N; Liu, X; Curran, E H; O'Neil, S P

    2008-11-01

    A 20-year old male cotton-top tamarin (Saguinus oedipus) was presented with unilateral enlargement of an intrascrotal testicle. Fine-needle aspiration cytology demonstrated a neoplastic population with Call-Exner-like bodies and features of malignancy. The animal was castrated, and histologic examination revealed a biphasic sex cord-stromal tumor, with one region resembling Sertoli-cell tumor and one region resembling granulosa-cell tumor, with extensive microfollicular pattern and many Call-Exner bodies. Eight months after castration, the animal was euthanized on discovery of a caudal abdominal mass that displaced organs, was highly infiltrative, and extended into the paravertebral musculature with lysis of vertebral bone. Metastases to lymph node and lung were also present. Histologic examination of the abdominal tumor showed multifocal formation of Call-Exner bodies in an otherwise highly dedifferentiated population. Positive immunolabeling for alpha inhibin confirmed the sex cord-stromal origin of the abdominal and paravertebral tumor masses. This case has similarities to malignant testicular granulosa-cell tumor of humans.

  8. Twist1 in tumor cells and α-smooth muscle actin in stromal cells are possible biomarkers for metastatic giant basal cell carcinoma.

    PubMed

    Motegi, Sei-ichiro; Yamada, Kazuya; Ishikawa, Osamu

    2013-08-01

    We previously reported a case of giant basal cell carcinoma (BCC) in a 75-year-old Japanese man, who subsequently developed a pulmonary metastasis. With regard to the pathogenesis of metastasis of BCC, recently, it has been reported that high levels of expression of Twist1 and N-cadherin in primary and metastatic tumor cells, suggesting that Twist1 expression and an epithelial-mesenchymal transition (EMT) of tumor cells are important for the promotion of tumor invasion and subsequent metastasis. In this report, we identified the expressions of Twist1 in tumor cells and α-smooth muscle actin (α-SMA) in stromal cells in the primary and metastatic sites of giant BCC. These results suggest that Twist1-induced EMT of tumor cells might have been associated with distant organ metastasis in our case, and the presence of α-SMA-positive myofibroblasts surrounding a BCC nest can be one of hallmarks of the aggressiveness of BCC.

  9. Periostin expression in intra-tumoral stromal cells is prognostic and predictive for colorectal carcinoma via creating a cancer-supportive niche

    PubMed Central

    Tan, Xiaojie; Ding, Yibo; Luo, Yanxin; Cai, Hui; Liu, Yan; Gao, Xianhua; Liu, Qizhi; Yu, Yongwei; Du, Yan; Wang, Hao; Ma, Liye; Wang, Jianping; Chen, Kun; Ding, Yanqing; Fu, Chuangang; Cao, Guangwen

    2016-01-01

    Periostin (POSTN) expression in cancer cells and circulation has been related to poor prognosis of colorectal carcinoma (CRC). However, the role of POSTN expressed in intra-tumoral stroma on CRC progression remains largely unknown. This study enrolled 1098 CRC patients who received surgical treatment in Shanghai and Guangzhou, Mainland China. In Shanghai cohort, immunohistochemistry score of stromal POSTN expression increased consecutively from adjacent mucosa, primary CRC tissues, to metastatic CRC tissues (P < 0.001), while medium- and high-stromal POSTN expression, rather than epithelial POSTN expression, independently predicted unfavorable prognoses of CRC, adjusted for covariates including TNM stage and postoperative chemotherapy in multivariate Cox models. The results in Shanghai cohort were faithfully replicated in Guangzhou cohort. Stromal POSTN expression dose-dependently predicted an unfavorable prognosis of stage III CRC patients with postoperative chemotherapy in both cohorts. POSTN derived from colonic fibroblasts or recombinant POSTN significantly promoted proliferation, anchorage independent growth, invasion, and chemo-resistance of CRC cells; whereas these effects were counteracted via targeting to PI3K/Akt or Wnt/β-catenin signaling pathway. CRC cell RKO-derived factor(s) significantly induced POSTN production in colonic fibroblasts and autocrine POSTN promoted proliferation, migration, and anchorage independent growth of fibroblasts. Conclusively, stromal POSTN is prognostic and predictive for CRC via creating a niche to facilitate cancer progression. Targeting POSTN-induced signaling pathways may be therapeutic options for metastatic or chemoresistant CRC. PMID:26556874

  10. Stromal interaction molecule 1 (STIM1) silencing inhibits tumor growth and promotes cell cycle arrest and apoptosis in hypopharyngeal carcinoma.

    PubMed

    Sun, Yuanhao; Cui, Xiaobo; Wang, Jun; Wu, Shuai; Bai, Yunfei; Wang, Yaping; Wang, Boqian; Fang, Jugao

    2015-05-01

    As an important pathway maintaining the balance of intracellular calcium (Ca(2+)), store-operated Ca(2+) entry (SOCE) is critical for cellular functions. Stromal interaction molecule 1 (STIM1), a key component of SOCE, plays a dual role as an endoplasmic reticulum Ca(2+) receptor and an SOCE exciter. Aberrant expression of STIM1 could be discovered in several human cancer cells. However, the role of STIM1 in regulating human hypopharyngeal carcinoma still remains unclear. Real-time polymerase chain reaction (PCR) was used to detect expression of STIM1 in human hypopharyngeal carcinoma cell line FaDu. STIM1 on FaDu cells was knocked down by lentiviral transduction method. The biological impacts after knocking down of STIM1 on FaDu cells were investigated in vitro and in vivo. The result of real-time PCR showed that STIM1 was expressed in FaDu cells. Lentiviral transduction efficiently downregulated the expression of STIM1 in FaDu cells at both mRNA and protein levels. Significant downregulation of STIM1 on FaDu cells inhibited cell proliferation, induced cell cycle arrest in G0/G1 phase, promoted cell apoptosis, and restrained cell growth rate. The antigrowth effect of STIM1 silencing was also discovered in FaDu hypopharyngeal tumor model. Our findings indicate that STIM1 is likely to become a new therapeutic target for hypopharyngeal carcinoma treatment.

  11. Biologically relevant 3D tumor arrays: treatment response and the importance of stromal partners

    NASA Astrophysics Data System (ADS)

    Rizvi, Imran; Celli, Jonathan P.; Xu, Feng; Evans, Conor L.; Abu-Yousif, Adnan O.; Muzikansky, Alona; Elrington, Stefan A.; Pogue, Brian W.; Finkelstein, Dianne M.; Demirci, Utkan; Hasan, Tayyaba

    2011-02-01

    The development and translational potential of therapeutic strategies for cancer is limited, in part, by a lack of biological models that capture important aspects of tumor growth and treatment response. It is also becoming increasingly evident that no single treatment will be curative for this complex disease. Rationally-designed combination regimens that impact multiple targets provide the best hope of significantly improving clinical outcomes for cancer patients. Rapidly identifying treatments that cooperatively enhance treatment efficacy from the vast library of candidate interventions is not feasible, however, with current systems. There is a vital, unmet need to create cell-based research platforms that more accurately mimic the complex biology of human tumors than monolayer cultures, while providing the ability to screen therapeutic combinations more rapidly than animal models. We have developed a highly reproducible in vitro three-dimensional (3D) tumor model for micrometastatic ovarian cancer (OvCa), which in conjunction with quantitative image analysis routines to batch-process large datasets, serves as a high throughput reporter to screen rationally-designed combination regimens. We use this system to assess mechanism-based combination regimens with photodynamic therapy (PDT), which sensitizes OvCa to chemo and biologic agents, and has shown promise in clinic trials. We show that PDT synergistically enhances carboplatin efficacy in a sequence dependent manner. In printed heterocellular cultures we demonstrate that proximity of fibroblasts enhances 3D tumor growth and investigate co-cultures with endothelial cells. The principles described here could inform the design and evaluation of mechanism-based therapeutic options for a broad spectrum of metastatic solid tumors.

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

    PubMed

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

    2016-08-07

    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

  13. Diagnosis and management of gastrointestinal neuroendocrine tumors: An evidence-based Canadian consensus.

    PubMed

    Singh, Simron; Asa, Sylvia L; Dey, Chris; Kennecke, Hagen; Laidley, David; Law, Calvin; Asmis, Timothy; Chan, David; Ezzat, Shereen; Goodwin, Rachel; Mete, Ozgur; Pasieka, Janice; Rivera, Juan; Wong, Ralph; Segelov, Eva; Rayson, Daniel

    2016-06-01

    The majority of neuroendocrine tumors originate in the digestive system and incidence is increasing within Canada and globally. Due to rapidly evolving evidence related to diagnosis and clinical management, updated guidance on the diagnosis and treatment of gastrointestinal neuroendocrine tumors (GI-NETs) are of clinical importance. Well-differentiated GI-NETs may exhibit indolent clinical behavior and are often metastatic at diagnosis. Some NET patients will develop secretory disease requiring symptom control to optimize quality of life and clinical outcomes. Optimal management of GI-NETs is in a multidisciplinary environment and is multimodal, requiring collaboration between medical, surgical, imaging and pathology specialties. Clinical application of advances in pathological classification and diagnostic technologies, along with evolving surgical, radiotherapeutic and medical therapies are critical to the advancement of patient care. We performed a systematic literature search to update our last set of published guidelines (2010) and identified new level 1 evidence for novel therapies, including telotristat etiprate (TELESTAR), lanreotide (CLARINET), everolimus (RADIANT-2; RADIANT-4) and peptide receptor radionuclide therapy (PRRT; NETTER-1). Integrating these data with the clinical knowledge of 16 multi-disciplinary experts, we devised consensus recommendations to guide state of the art clinical management of GI-NETs.

  14. Recombinant erythropoietin for the anaemia of patients with advanced Gastrointestinal Stromal Tumours (GIST) receiving imatinib: an active agent only in non progressive patients

    PubMed Central

    2012-01-01

    Abstract Recombinant erythropoietin for the anaemia of patients with advanced Gastrointestinal Stromal Tumours (GIST) receiving imatinib : an active agent only in non progressive patients. Background Imatinib is a standard treatment for advanced/metastatic GIST and in adjuvant setting. Anaemia is frequently observed in patients with advanced GIST, and is one of the most frequent side effects of imatinib with grade 3–4 anaemia in 10% of patients. Whether EPO treatment is useful in the management of GIST patients receiving imatinib treatment is unknown. Methods A retrospective study of EPO treatment in GIST patients receiving imatinib was undertaken in 4 centres. Thirty four patients received EPO treatment among the 319 GIST patients treated with imatinib in clinical trials or with compassionate use between 2001 and 2003. The efficacy of EPO on the anaemia of patients with GIST treated with imatinib was analyzed. Results There were 18 males and 16 females with a median age of 59 years. Median WHO-PS was 1. Primary tumour sites were mainly gastric (32%) and small bowel (29%). Sites of metastases were mainly liver (82%) and peritoneum (79%). The median delay between the initiation of imatinib treatment and EPO was 58 days (range 0–553). Median haemoglobin (Hb) level prior to EPO was 9 g/dL (range 6,9-11,8) and 11,7 g/dL (range 6,8-14,4) after 2 months. An increase of more than 2 g/dL was observed in 18 (53%) of patients. None of the 7 patients who progressed (PD) under imatinib treatment (400 mg/day) experienced HB response, as compared to 66% (18/27) of the remaining patients (PR + SD) (p = 0,002). Primary tumour site, liver metastases, peritoneal metastases, age, gender did not correlate with HB response to EPO. Response to EPO was observed in 2/11 patients receiving high-dose imatinib (800 mg/day) vs 16/23 of others. Using logistic regression, only PD before EPO treatment was retained as a predictive factor for EPO response. Conclusion EPO enables to

  15. Advanced Imaging Approaches to Characterize Stromal and Metabolic Changes in in Vivo Mammary Tumor Models

    DTIC Science & Technology

    2014-03-01

    then locks into the microscope stage for extreme stability. Extremely stable intravital images can then be collected with nearly no breathing...Szulczewski, PJ Keely, KW Eliceiri. Novel Intravital Imaging Approaches to Characterize Collagen Alignment in Defined Mammary Tumor Models. Microscopy and...repeated 3 times on different days. 13   Figure 5: New fixturing for intravital FLIM imaging through a rodent mammary imaging window. Stage is raised

  16. Gastrointestinal hormones stimulate growth of Foregut Neuroendocrine Tumors by transactivating the EGF receptor.

    PubMed

    Di Florio, Alessia; Sancho, Veronica; Moreno, Paola; Delle Fave, Gianfranco; Jensen, Robert T

    2013-03-01

    Foregut neuroendocrine tumors [NETs] usually pursuit a benign course, but some show aggressive behavior. The treatment of patients with advanced NETs is marginally effective and new approaches are needed. In other tumors, transactivation of the EGF receptor (EGFR) by growth factors, gastrointestinal (GI) hormones and lipids can stimulate growth, which has led to new treatments. Recent studies show a direct correlation between NET malignancy and EGFR expression, EGFR inhibition decreases basal NET growth and an autocrine growth effect exerted by GI hormones, for some NETs. To determine if GI hormones can stimulate NET growth by inducing transactivation of EGFR, we examined the ability of EGF, TGFα and various GI hormones to stimulate growth of the human foregut carcinoid,BON, the somatostatinoma QGP-1 and the rat islet tumor,Rin-14B-cell lines. The EGFR tyrosine-kinase inhibitor, AG1478 strongly inhibited EGF and the GI hormones stimulated cell growth, both in BON and QGP-1 cells. In all the three neuroendocrine cell lines studied, we found EGF, TGFα and the other growth-stimulating GI hormones increased Tyr(1068) EGFR phosphorylation. In BON cells, both the GI hormones neurotensin and a bombesin analogue caused a time- and dose-dependent increase in EGFR phosphorylation, which was strongly inhibited by AG1478. Moreover, we found this stimulated phosphorylation was dependent on Src kinases, PKCs, matrix metalloproteinase activation and the generation of reactive oxygen species. These results raise the possibility that disruption of this signaling cascade by either EGFR inhibition alone or combined with receptor antagonists may be a novel therapeutic approach for treatment of foregut NETs/PETs.

  17. Gastrointestinal hormones stimulate growth of Foregut Neuroendocrine Tumors by transactivating the EGF receptor

    PubMed Central

    Di Florio, Alessia; Sancho, Veronica; Moreno, Paola; Fave, Gianfranco Delle; Jensen, Robert T.

    2012-01-01

    Foregut Neuroendocrine Tumors[NETs] usually pursuit a benign course, but some show aggressive behavior. The treatment of patients with advanced NETs is marginally effective and new approaches are needed. In other tumors, transactivation of the EGF receptor(EGFR) by growth factors, gastrointestinal(GI) hormones and lipids can stimulate growth, which has led to new treatments. Recent studies show a direct correlation between NET malignancy and EGFR expression, EGFR inhibition decreases basal NET growth and an autocrine growth effect exerted by GI hormones, for some NETs. To determine if GI hormones can stimulate NET growth by inducing transactivation of EGFR, we examined the ability of EGF, TGFα and various GI hormones to stimulate growth of the human foregut carcinoid, BON, the somatostatinoma QGP-1 and the rat islet tumor, Rin-14B-cell lines. The EGFR tyrosine-kinase inhibitor, AG1478 strongly inhibited EGF and the GI hormones stimulated cell growth, both in BON and QGP-1 cells. In all the three neuroendocrine cell lines studied, we found EGF, TGFα and the other growth-stimulating GI hormones increased Tyr1068 EGFR phosphorylation. In BON cells, both the GI hormones neurotensin and a bombesin analogue caused a time- and dose-dependent increase in EGFR phosphorylation, which was strongly inhibited by AG1478. Moreover, we found this stimulated phosphorylation was dependent on Src kinases, PKCs, matrix metalloproteinase activation and the generation of reactive oxygen species. These results raise the possibility that disruption of this signaling cascade by either EGFR inhibition alone or combined with receptor antagonists may be a novel therapeutic approach for treatment of foregut NETs/PETs. PMID:23220008

  18. Tumor necrosis factor improves vascularization in osteogenic grafts engineered with human adipose-derived stem/stromal cells.

    PubMed

    Hutton, Daphne L; Kondragunta, Renu; Moore, Erika M; Hung, Ben P; Jia, Xiaofeng; Grayson, Warren L

    2014-01-01

    The innate immune response following bone injury plays an important role in promoting cellular recruitment, revascularization, and other repair mechanisms. Tumor necrosis factor-α (TNF) is a prominent pro-inflammatory cytokine in this cascade, and has been previously shown to improve bone formation and angiogenesis in a dose- and timing-dependent manner. This ability to positively impact both osteogenesis and vascular growth may benefit bone tissue engineering, as vasculature is essential to maintaining cell viability in large grafts after implantation. Here, we investigated the effects of exogenous TNF on the induction of adipose-derived stem/stromal cells (ASCs) to engineer pre-vascularized osteogenic tissue in vitro with respect to dose, timing, and co-stimulation with other inflammatory mediators. We found that acute (2-day), low-dose exposure to TNF promoted vascularization, whereas higher doses and continuous exposure inhibited vascular growth. Co-stimulation with platelet-derived growth factor (PDGF), another key factor released following bone injury, increased vascular network formation synergistically with TNF. ASC-seeded grafts were then cultured within polycaprolactone-fibrin composite scaffolds and implanted in nude rats for 2 weeks, resulting in further tissue maturation and increased angiogenic ingrowth in TNF-treated grafts. VEGF-A expression levels were significantly higher in TNF-treated grafts immediately prior to implantation, indicating a long-term pro-angiogenic effect. These findings demonstrate that TNF has the potential to promote vasculogenesis in engineered osteogenic grafts both in vitro and in vivo. Thus, modulation and/or recapitulation of the immune response following bone injury may be a beneficial strategy for bone tissue engineering.

  19. Interferon-γ differentially modulates the impact of tumor necrosis factor-α on human endometrial stromal cells.

    PubMed

    Spratte, Julia; Oemus, Anne; Zygmunt, Marek; Fluhr, Herbert

    2015-09-01

    The pro-inflammatory T helper (Th)-1 cytokines, tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ), are immunological factors relevant at the feto-maternal interface and involved in the pathophysiology of implantation disorders. The synergistic action of the two cytokines has been described with regard to apoptotic cell death and inflammatory responses in different cell types, but little is known regarding the human endometrium. Therefore, we examined the interaction of TNF-α and IFN-γ in human endometrial stromal cells (ESCs). ESCs were isolated from specimens obtained during hysterectomy and decidualized in vitro. Cells were incubated with TNF-α, IFN-γ or signaling-inhibitor. Insulin-like growth factor binding protein (IGFBP)-1, prolactin (PRL), leukemia inhibitory factor (LIF), interleukin (IL)-6, IL-8, regulated on activation normal T-cell expressed and secreted protein (RANTES) and monocyte chemotactic protein (MCP)-1 were measured using ELISA and real-time RT-PCR. Nuclear factor of transcription (NF)-κB and its inhibitor (IκBα) were analyzed by in-cell western assay and transcription factor assay. TNF-α inhibited and IFN-γ did not affect the decidualization of ESCs. In contrast, IFN-gamma differentially modulated the stimulating effect of TNF-alpha on cytokines by enhancing IL-6, RANTES and MCP-1 and attenuating LIF mRNA expression. These effects were time- and dose-dependent. IFN-γ had no impact on the initial activation of NF-κB signaling. Histone-deacetylase activity was involved in the modulating effect of IFN-γ on RANTES secretion. These observations showed a distinct pattern of interaction of the Th-1 cytokines, TNF-α and IFN-γ in the human endometrium, which could play an important role in the pathophysiology of implantation disorders.

  20. Microcystic Stromal Tumor: A Distinctive Ovarian Sex Cord-Stromal Neoplasm Characterized by FOXL2, SF-1, WT-1, Cyclin D1, and β-catenin Nuclear Expression and CTNNB1 Mutations.

    PubMed

    Irving, Julie A; Lee, Cheng-Han; Yip, Stephen; Oliva, Esther; McCluggage, W Glenn; Young, Robert H

    2015-10-01

    Since our first description of the microcystic stromal tumor (MST) of the ovary, a rare and distinctive neoplasm with a definitional, usually striking microcystic pattern and a CD10+/vimentin+/inhibin-/calretinin- immunophenotype, 3 examples with β-catenin nuclear localization, and CTNNB1 mutation have been reported. We undertook a detailed immunohistochemical study and molecular analysis of CTNNB1 and FOXL2 of 15 cases of MST to further characterize this neoplasm and establish its histogenesis. Diffuse nuclear staining for FOXL2, WT-1, cyclin D1, and β-catenin was present in all tumors tested, and 12/15 were positive for steroidogenic factor-1 (SF-1). Heterozygous missense point mutations in exon 3 of CTNNB1 were detected in 8 of 14 cases, resulting in amino acid changes at codons 32, 34, 35, and 37. There was no correlation between CTNNB1 exon 3 mutation status and tumor immunophenotype. All 14 cases tested showed wild-type FOXL2. Our study establishes that MST of the ovary exhibits a characteristic FOXL2/SF-1/WT-1/cyclin D1/nuclear β-catenin-positive immunohistochemical profile, which may be useful in diagnosis and in the exclusion of histologic mimics. The presence of diffuse nuclear FOXL2 and WT-1 immunostaining in all cases and SF-1 in most supports the classification of MST within the sex cord-stromal category. Aberrant nuclear β-catenin expression, detected in all MSTs, appears to be the result of stabilizing CTNNB1 mutations in 57% of cases, providing further evidence that dysregulation of the Wnt/B-catenin pathway is involved in the tumorigenesis of MST and may involve activation of β-catenin with upregulation of cyclin D1.

  1. The Initiator Methionine tRNA Drives Secretion of Type II Collagen from Stromal Fibroblasts to Promote Tumor Growth and Angiogenesis.

    PubMed

    Clarke, Cassie J; Berg, Tracy J; Birch, Joanna; Ennis, Darren; Mitchell, Louise; Cloix, Catherine; Campbell, Andrew; Sumpton, David; Nixon, Colin; Campbell, Kirsteen; Bridgeman, Victoria L; Vermeulen, Peter B; Foo, Shane; Kostaras, Eleftherios; Jones, J Louise; Haywood, Linda; Pulleine, Ellie; Yin, Huabing; Strathdee, Douglas; Sansom, Owen; Blyth, Karen; McNeish, Iain; Zanivan, Sara; Reynolds, Andrew R; Norman, Jim C

    2016-03-21

    Expression of the initiator methionine tRNA (tRNAi(Met)) is deregulated in cancer. Despite this fact, it is not currently known how tRNAi(Met) expression levels influence tumor progression. We have found that tRNAi(Met) expression is increased in carcinoma-associated fibroblasts, implicating deregulated expression of tRNAi(Met) in the tumor stroma as a possible contributor to tumor progression. To investigate how elevated stromal tRNAi(Met) contributes to tumor progression, we generated a mouse expressing additional copies of the tRNAi(Met) gene (2+tRNAi(Met) mouse). Growth and vascularization of subcutaneous tumor allografts was enhanced in 2+tRNAi(Met) mice compared with wild-type littermate controls. Extracellular matrix (ECM) deposited by fibroblasts from 2+tRNAi(Met) mice supported enhanced endothelial cell and fibroblast migration. SILAC mass spectrometry indicated that elevated expression of tRNAi(Met) significantly increased synthesis and secretion of certain types of collagen, in particular type II collagen. Suppression of type II collagen opposed the ability of tRNAi(Met)-overexpressing fibroblasts to deposit pro-migratory ECM. We used the prolyl hydroxylase inhibitor ethyl-3,4-dihydroxybenzoate (DHB) to determine whether collagen synthesis contributes to the tRNAi(Met)-driven pro-tumorigenic stroma in vivo. DHB had no effect on the growth of syngeneic allografts in wild-type mice but opposed the ability of 2+tRNAi(Met) mice to support increased angiogenesis and tumor growth. Finally, collagen II expression predicts poor prognosis in high-grade serous ovarian carcinoma. Taken together, these data indicate that increased tRNAi(Met) levels contribute to tumor progression by enhancing the ability of stromal fibroblasts to synthesize and secrete a type II collagen-rich ECM that supports endothelial cell migration and angiogenesis.

  2. Tumor-initiating label-retaining cancer cells in human gastrointestinal cancers undergo asymmetric cell division.

    PubMed

    Xin, Hong-Wu; Hari, Danielle M; Mullinax, John E; Ambe, Chenwi M; Koizumi, Tomotake; Ray, Satyajit; Anderson, Andrew J; Wiegand, Gordon W; Garfield, Susan H; Thorgeirsson, Snorri S; Avital, Itzhak

    2012-04-01

    Label-retaining cells (LRCs) have been proposed to represent adult tissue stem cells. LRCs are hypothesized to result from either slow cycling or asymmetric cell division (ACD). However, the stem cell nature and whether LRC undergo ACD remain controversial. Here, we demonstrate label-retaining cancer cells (LRCCs) in several gastrointestinal (GI) cancers including fresh surgical specimens. Using a novel method for isolation of live LRCC, we demonstrate that a subpopulation of LRCC is actively dividing and exhibits stem cells and pluripotency gene expression profiles. Using real-time confocal microscopic cinematography, we show live LRCC undergoing asymmetric nonrandom chromosomal cosegregation LRC division. Importantly, LRCCs have greater tumor-initiating capacity than non-LRCCs. Based on our data and that cancers develop in tissues that harbor normal-LRC, we propose that LRCC might represent a novel population of GI stem-like cancer cells. LRCC may provide novel mechanistic insights into the biology of cancer and regenerative medicine and present novel targets for cancer treatment.

  3. Role of Endoscopic Ultrasonography in Guiding Treatment Plans for Upper Gastrointestinal Subepithelial Tumors.

    PubMed

    Moon, Jeong Seop

    2016-05-01

    Gastrointestinal (GI) subepithelial tumors (SETs) are usually observed incidentally by endoscopy and have diverse prognoses, varying from benign to potentially malignant. When a GI SET is suspected, endoscopic ultrasonography (EUS) is the most accurate diagnostic method to differentiate it from extraluminal compression. To determine the nature of GI SETs, EUS is also the most accurate diagnostic method, and reveals the precise sonographic nature of the lesion. There are some SETs with typical EUS findings of GI SETs, but most hypoechoic lesions are difficult to diagnose based on EUS images alone. EUS is also helpful to determine GI wall involvement in SETs and optimal treatment methods. For the diagnosis of GI SETs, obtaining a proper specimen is essential. EUS-guided cytology or biopsy methods such as fine-needle aspiration, Tru-Cut biopsy, and the newly introduced fine-needle biopsy (FNB) provide good results. To increase the diagnostic yield for GI SETs, cytology with immunocytochemical staining is used for cytological interpretation, resulting in good diagnostic yields. Recently, EUS-FNB using cheese slicer technology has been introduced, and has been reported to provide good diagnostic results for GI SETs.

  4. Laparoscopic Treatment of Sclerosing Stromal Tumor of the Ovary in a Woman With Gorlin-Goltz Syndrome: A Case Report and Review of the Literature.

    PubMed

    Grechi, Gianluca; Clemente, Nicolò; Tozzi, Alessandra; Ciavattini, Andrea

    2015-01-01

    Gorlin-Goltz syndrome is a rare hereditary multisystemic disease. Multiple basal cell carcinomas, odontogenic keratocysts, and skeletal abnormalities are the main clinical manifestations of the syndrome, but several organs can be involved. Moreover, this condition is associated with the development of various benign and malignant tumors, even in the genital tract. This report describes a rare association between Gorlin-Goltz syndrome and the sclerosing stromal tumor of the ovary. Because the ultrasound and magnetic resonance imaging patterns of this tumor can be similar to those of a malignant neoplasm, prompt surgical intervention and histological confirmation of diagnosis is mandatory; however, this is a benign lesion and thus can be approached with a laparoscopic fertility-sparing surgery. Gynecologists should be aware of this possible association to provide appropriate counseling for these women, and to take a fertility-sparing laparoscopic approach whenever possible.

  5. Dislodgement and gastrointestinal tract penetration of bone cement used for spinal reconstruction after lumbosacral vertebral tumor excision

    PubMed Central

    Nagae, Masateru; Mikami, Yasuo; Mizuno, Kentaro; Harada, Tomohisa; Ikeda, Takumi; Tonomura, Hitoshi; Takatori, Ryota; Fujiwara, Hiroyoshi; Kubo, Toshikazu

    2016-01-01

    Abstract Introduction: Polymethylmethacrylate (PMMA) cement is useful for spinal reconstruction, but can cause complications including new vertebral fractures, neurological disorders and pulmonary embolism. We report a case in PMMA cement used for spinal reconstruction after tumor curettage dislodged and penetrated the gastrointestinal tract. Diagnoses: The patient was diagnosed with a retroperitoneal extragonadal germ cell tumor at age 27 years. After chemotherapy and tumor resection, the tumor remained. It gradually increased in size and infiltrated lumbosacral vertebrae, causing him to present at age 35 years with increased low back pain. Image findings showed bone destruction in the vertebral bodies accompanied by neoplastic lesions. The left and right common iliac arteries and inferior vena cava were enclosed in the tumor on the anterior side of the vertebral bodies. Lumbosacral bone tumor due to direct extragonadal germ cell tumor infiltration was diagnosed. A 2-step operation was planned; first, fixation of the posterior side of the vertebral bodies, followed by tumor resection using an anterior transperitoneal approach, and spinal reconstruction using PMMA cement. After surgery, the PMMA cement gradually dislodged towards the anterior side and, 2 years 9 months after surgery, it had penetrated the retroperitoneum. The patient subsequently developed nausea and abdominal pain and was readmitted to hospital. The diagnosis was intestinal blockage with dislodged PMMA cement, and an operation was performed to remove the cement present in the small intestine. There was strong intra-abdominal adhesion, the peritoneum between the vertebral bodies and intestine could not be identified, and no additional treatment for vertebral body defects could be performed. After surgery, gastrointestinal symptoms resolved. Conclusion: Although this was a rare case, when using bone cement for vertebral body reconstruction, the way of anchoring for the cement must be thoroughly

  6. Glycolytic cancer associated fibroblasts promote breast cancer tumor growth, without a measurable increase in angiogenesis: evidence for stromal-epithelial metabolic coupling.

    PubMed

    Migneco, Gemma; Whitaker-Menezes, Diana; Chiavarina, Barbara; Castello-Cros, Remedios; Pavlides, Stephanos; Pestell, Richard G; Fatatis, Alessandro; Flomenberg, Neal; Tsirigos, Aristotelis; Howell, Anthony; Martinez-Outschoorn, Ubaldo E; Sotgia, Federica; Lisanti, Michael P

    2010-06-15

    Previously, we proposed a new model for understanding the Warburg effect in tumorigenesis and metastasis. In this model, the stromal fibroblasts would undergo aerobic glycolysis (a.k.a., the Warburg effect)--producing and secreting increased pyruvate/lactate that could then be used by adjacent epithelial cancer cells as "fuel" for the mitochondrial TCA cycle, oxidative phosphorylation, and ATP production. To test this model more directly, here we used a matched set of metabolically well-characterized immortalized fibroblasts that differ in a single gene. CL3 fibroblasts show a shift towards oxidative metabolism, and have an increased mitochondrial mass. In contrast, CL4 fibroblasts show a shift towards aerobic glycolysis, and have a reduced mitochondrial mass. We validated these differences in CL3 and CL4 fibroblasts by performing an unbiased proteomics analysis, showing the functional upregulation of 4 glycolytic enzymes, namely ENO1, ALDOA, LDHA and TPI1, in CL4 fibroblasts. Many of the proteins that were upregulated in CL4 fibroblasts, as seen by unbiased proteomics, were also transcriptionally upregulated in the stroma of human breast cancers, especially in the patients that were prone to metastasis. Importantly, when CL4 fibroblasts were co-injected with human breast cancer cells (MDA-MB-231) in a xenograft model, tumor growth was dramatically enhanced. CL4 fibroblasts induced a > 4-fold increase in tumor mass, and a near 8-fold increase in tumor volume, without any measurable increases in tumor angiogenesis. In parallel, CL3 and CL4 fibroblasts both failed to form tumors when they were injected alone, without epithelial cancer cells. Mechanistically, under co-culture conditions, CL4 glycolytic fibroblasts increased mitochondrial activity in adjacent breast cancer cells (relative to CL3 cells), consistent with the "Reverse Warburg Effect". Notably, Western blot analysis of CL4 fibroblasts revealed a significant reduction in caveolin-1 (Cav-1) protein levels

  7. Regulation of IL-6 and IL-8 production by reciprocal cell-to-cell interactions between tumor cells and stromal fibroblasts through IL-1α in ameloblastoma

    SciTech Connect

    Fuchigami, Takao; Kibe, Toshiro; Koyama, Hirofumi; Kishida, Shosei; Iijima, Mikio; Nishizawa, Yoshiaki; Hijioka, Hiroshi; Fujii, Tomomi; Ueda, Masahiro; Nakamura, Norifumi; Kiyono, Tohru; Kishida, Michiko

    2014-09-05

    Highlights: • We studied the interaction between tumor cells and fibroblasts in ameloblastoma. • AM-3 ameloblastoma cells secreted significantly high IL-1α levels. • IL-1α derived from AM-3 cells promoted IL-6 and IL-8 secretion of fibroblasts. • IL-6 and IL-8 activated the cellular motility and proliferation of AM-3 cells. - Abstract: Ameloblastoma is an odontogenic benign tumor that occurs in the jawbone, which invades bone and reoccurs locally. This tumor is treated by wide surgical excision and causes various problems, including changes in facial countenance and mastication disorders. Ameloblastomas have abundant tumor stroma, including fibroblasts and immune cells. Although cell-to-cell interactions are considered to be involved in the pathogenesis of many diseases, intercellular communications in ameloblastoma have not been fully investigated. In this study, we examined interactions between tumor cells and stromal fibroblasts via soluble factors in ameloblastoma. We used a human ameloblastoma cell line (AM-3 ameloblastoma cells), human fibroblasts (HFF-2 fibroblasts), and primary-cultured fibroblasts from human ameloblastoma tissues, and analyzed the effect of ameloblastoma-associated cell-to-cell communications on gene expression, cytokine secretion, cellular motility and proliferation. AM-3 ameloblastoma cells secreted higher levels of interleukin (IL)-1α than HFF-2 fibroblasts. Treatment with conditioned medium from AM-3 ameloblastoma cells upregulated gene expression and secretion of IL-6 and IL-8 of HFF-2 fibroblasts and primary-cultured fibroblast cells from ameloblastoma tissues. The AM3-stimulated production of IL-6 and IL-8 in fibroblasts was neutralized by pretreatment of AM-3 cells with anti-IL-1α antibody and IL-1 receptor antagonist. Reciprocally, cellular motility of AM-3 ameloblastoma cells was stimulated by HFF-2 fibroblasts in IL-6 and IL-8 dependent manner. In conclusion, ameloblastoma cells and stromal fibroblasts behave

  8. Tumor markers for diagnosis, monitoring of recurrence and prognosis in patients with upper gastrointestinal tract cancer.

    PubMed

    Jing, Jie-Xian; Wang, Yan; Xu, Xiao-Qin; Sun, Ting; Tian, Bao-Guo; Du, Li-Li; Zhao, Xian-Wen; Han, Cun-Zhi

    2014-01-01

    To evaluate the value of combined detection of serum CEA, CA19-9, CA24-2, AFP, CA72-4, SCC, TPA and TPS for the clinical diagnosis of upper gastrointestinal tract (GIT) cancer and to analyze the efficacy of these tumor markers (TMs) in evaluating curative effects and prognosis. A total of 573 patients with upper GIT cancer between January 2004 and December 2007 were enrolled in this study. Serum levels of CEA, CA19-9, CA24-2, AFP, CA72-4, SCC, TPA and TPS were examined preoperatively and every 3 months postoperatively by ELISA. The sensitivity of CEA, CA19-9, CA24-2, AFP, CA72-4, SCC, TPA and TPS were 26.8%, 36.2%, 42.9%, 2.84%, 25.4%, 34.6%, 34.2% and 30.9%, respectively. The combined detection of CEA+CA199+CA242+CA724 had higher sensitivity and specificity in gastric cancer (GC) and cardiac cancer, while CEA+CA199+CA242+SCC was the best combination of diagnosis for esophageal cancer (EC). Elevation of preoperative CEA, CA19-9 and CA24-2, SCC and CA72-4 was significantly associated with pathological types (p<0.05) and TNM staging (p<0.05). Correlation analysis showed that CA24-2 was significantly correlated with CA19-9 (r=0.810, p<0.001). The levels of CEA, CA19-9, CA24-2, CA72-4 and SCC decreased obviously 3 months after operations. When metastasis and recurrence occurred, the levels of TMs significantly increased. On multivariate analysis, high preoperative CA72-4, CA24-2 and SCC served as prognostic factors for cardiac carcinoma, GC and EC, respectively. combined detection of CEA+CA199+CA242+SCC proved to be the most economic and practical strategy in diagnosis of EC; CEA+CA199+CA242+CA724 proved to be a better evaluation indicator for cardiac cancer and GC. CEA and CA19-9, CA24-2, CA72-4 and SCC, examined postoperatively during follow-up, were useful to find early tumor recurrence and metastasis, and evaluate prognosis. AFP, TPA and TPS have no significant value in diagnosis of patients with upper GIT cancer.

  9. RNA Sequencing of Tumor-Associated Microglia Reveals Ccl5 as a Stromal Chemokine Critical for Neurofibromatosis-1 Glioma Growth1

    PubMed Central

    Solga, Anne C.; Pong, Winnie W.; Kim, Keun-Young; Cimino, Patrick J.; Toonen, Joseph A.; Walker, Jason; Wylie, Todd; Magrini, Vincent; Griffith, Malachi; Griffith, Obi L.; Ly, Amy; Ellisman, Mark H.; Mardis, Elaine R.; Gutmann, David H.

    2015-01-01

    Solid cancers develop within a supportive microenvironment that promotes tumor formation and growth through the elaboration of mitogens and chemokines. Within these tumors, monocytes (macrophages and microglia) represent rich sources of these stromal factors. Leveraging a genetically engineered mouse model of neurofibromatosis type 1 (NF1) low-grade brain tumor (optic glioma), we have previously demonstrated that microglia are essential for glioma formation and maintenance. To identify potential tumor-associated microglial factors that support glioma growth (gliomagens), we initiated a comprehensive large-scale discovery effort using optimized RNA-sequencing methods focused specifically on glioma-associated microglia. Candidate microglial gliomagens were prioritized to identify potential secreted or membrane-bound proteins, which were next validated by quantitative real-time polymerase chain reaction as well as by RNA fluorescence in situ hybridization following minocycline-mediated microglial inactivation in vivo. Using these selection criteria, chemokine (C-C motif) ligand 5 (Ccl5) was identified as a chemokine highly expressed in genetically engineered Nf1 mouse optic gliomas relative to nonneoplastic optic nerves. As a candidate gliomagen, recombinant Ccl5 increased Nf1-deficient optic nerve astrocyte growth in vitro. Importantly, consistent with its critical role in maintaining tumor growth, treatment with Ccl5 neutralizing antibodies reduced Nf1 mouse optic glioma growth and improved retinal dysfunction in vivo. Collectively, these findings establish Ccl5 as an important microglial growth factor for low-grade glioma maintenance relevant to the development of future stroma-targeted brain tumor therapies. PMID:26585233

  10. Hereditary gastrointestinal cancer syndromes.

    PubMed

    Lynch, Henry T; Lynch, Jane F; Shaw, Trudy G

    2011-07-01

    The rapid growth of molecular genetics and its attendant germline mutation discoveries has enabled identification of persons who are at an inordinately high cancer risk and, therefore, ideal candidates for prevention. However, one must fully appreciate the extensive genotypic and phenotypic heterogeneity that exists in hereditary cancer. Once the causative germline mutation has been identified in a patient, high-risk members of the family can be similarly tested and identified and provided highly targeted surveillance and management opportunities. DNA testing can change the individual's presumed risk status and affect decision making by patients and their physicians regarding surveillance and management. Our purpose is to describe familial/hereditary cancers of the gastrointestinal tract, including familial Barrett's esophagus, hereditary diffuse gastric cancer, gastrointestinal stromal tumors, familial adenomatous polyposis and desmoid tumors, Lynch syndrome, small bowel cancer, and familial pancreatic cancer. We use our discussion of Lynch syndrome as a model for diagnostic and clinical translation strategies for all hereditary gastrointestinal tract cancers, which clearly can then be extended to cancer of all anatomic sites. Highly pertinent questions from the patient's perspective include the following: What kind of counseling will be provided to a patient with a Lynch syndrome mutation, and should that counseling be mandatory? Does the proband have the responsibility to inform relatives about the familial mutation, even if the relatives do not want to know whether they carry it? Is the patient is responsible for notifying family members that a parent or sibling has Lynch syndrome? Can notification be forced and, if so, under what circumstances? These questions point out the need for criteria regarding which family members to inform and how to inform them.

  11. Expression of betaglycan, an inhibin coreceptor, in normal human ovaries and ovarian sex cord-stromal tumors and its regulation in cultured human granulosa-luteal cells.

    PubMed

    Liu, Jianqi; Kuulasmaa, Tiina; Kosma, Veli-Matti; Bützow, Ralf; Vänttinen, Teemu; Hydén-Granskog, Christel; Voutilainen, Raimo

    2003-10-01

    Activins and inhibins are often antagonistic in the regulation of ovarian function. TGFbeta type III receptor, betaglycan, has been identified as a coreceptor to enhance the binding of inhibins to activin type II receptor and thus to prevent the binding of activins to their receptor. In this study we characterized the expression and regulation pattern of betaglycan gene in normal ovaries and sex cord-stromal tumors and in cultured human granulosa-luteal cells from women undergoing in vitro fertilization. Expression of betaglycan mRNA was detected by RT-PCR or Northern blotting in normal ovarian granulosa, thecal, and stroma cells as well as in granulosa-luteal cells. Immunohistochemical analysis revealed positive staining for betaglycan in antral and preovulatory follicular granulosa and thecal cells and in corpora lutea of normal ovaries. Furthermore, betaglycan expression was detected in the vast majority of granulosa cell tumors, thecomas, and fibromas, with weaker staining in granulosa cell tumors compared with fibrothecomas. In cultured granulosa-luteal cells, FSH and LH treatment increased dose-dependently the accumulation of betaglycan mRNA, as did the protein kinase A activator dibutyryl cAMP and the protein kinase C inhibitor staurosporine. In contrast, the protein kinase C activator 12-O-tetradecanoyl phorbol 13-acetate had no significant effect on betaglycan mRNA levels. Treatment with prostaglandin E(2) and with its receptor EP2 subtype agonist butaprost increased betaglycan mRNA accumulation and progesterone secretion dose- and time-dependently. In summary, betaglycan gene is expressed in normal human ovarian steroidogenic cells and sex cord-stromal ovarian tumors. The accumulation of its mRNA in cultured granulosa-luteal cells is up-regulated by gonadotropins and prostaglandin E(2), probably via the protein kinase A pathway. The specific expression and regulation pattern of betaglycan gene may be related to the functional antagonism of inhibins to

  12. 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.

    PubMed

    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.

  13. High expression of MAGE-A9 in tumor and stromal cells of non-small cell lung cancer was correlated with patient poor survival.

    PubMed

    Zhang, Siya; Zhai, Xiaolu; Wang, Gui; Feng, Jian; Zhu, Huijun; Xu, Liqin; Mao, Guoxin; Huang, Jianfei

    2015-01-01

    Melanoma associated antigen-A (MAGE-A) is an oncogene and correlated with tumor initiation and development. However the roles of MAGE-A9 in non-small cell lung cancer (NSCLC) are still unknown. We investigated MAGE-A9 mRNA expression in 18 tumor tissues of NSCLC by qRT-PCR and MAGE-A9 protein expression in 213 NSCLC samples of tissue arrays by immunohistochemical staining. We assessed the relationship between MAGE-A9 expression and clinical parameters. The results showed that the high expression of MAGE-A9 protein in NSCLC tumor cells were commonly present in squamous cell carcinomas (P = 0.030). It was also related to larger tumor diameter, lymph node metastasis and later stage grouping with TNM classification (all P < 0.05). Whereas the expression of MAGE-A9 in stromal cells was higher in squamous cell carcinomas as well. Cox regression univariate and multivariable analysis revealed that MAGE-A9 expression in tumor cells of NSCLC (P < 0.001) is an independent prognostic factor in five-year overall survival rate. We concluded that the molecular assessment of MAGEA9 could be considered to improve prognostic evaluation and to identify eligible patients for potential target therapy.

  14. Pregnancy-specific glycoprotein expression in normal gastrointestinal tract and in tumors detected with novel monoclonal antibodies.

    PubMed

    Houston, Aileen; Williams, John M; Rovis, Tihana Lenac; Shanley, Daniel K; O'Riordan, Ronan T; Kiely, Patrick A; Ball, Melanie; Barry, Orla P; Kelly, Jacquie; Fanning, Aine; MacSharry, John; Mandelboim, Ofer; Singer, Bernhard B; Jonjic, Stipan; Moore, Tom

    2016-01-01

    Pregnancy-specific glycoproteins (PSGs) are immunoglobulin superfamily members related to the carcinoembryonic antigen-related cell adhesion molecule (CEACAM) family and are encoded by 10 genes in the human. They are secreted at high levels by placental syncytiotrophoblast into maternal blood during pregnancy, and are implicated in immunoregulation, thromboregulation, and angiogenesis. To determine whether PSGs are expressed in tumors, we characterized 16 novel monoclonal antibodies to human PSG1 and used 2 that do not cross-react with CEACAMs to study PSG expression in tumors and in the gastrointestinal (GI) tract using tissue arrays and immunohistochemistry. Staining was frequently observed in primary squamous cell carcinomas and colonic adenocarcinomas and was correlated with the degree of tumor differentiation, being largely absent from metastatic samples. Staining was also observed in normal oesophageal and colonic epithelium. PSG expression in the human and mouse GI tract was confirmed using quantitative RT-PCR. However, mRNA expression was several orders of magnitude lower in the GI tract compared to placenta. Our results identify a non-placental site of PSG expression in the gut and associated tumors, with implications for determining whether PSGs have a role in tumor progression, and utility as tumor biomarkers.

  15. Ovarian Sertoli-Leydig cell tumor with heterologous elements of gastrointestinal type associated with elevated serum alpha-fetoprotein level: an unusual case and literature review

    PubMed Central

    Horta, Mariana; Cunha, Teresa Margarida; Marques, Rita Canas; Félix, Ana

    2014-01-01

    Here we describe the case of a 19-year-old woman with a poorly differentiated ovarian Sertoli-Leydig cell tumor and an elevated serum alpha-fetoprotein level. The patient presented with diffuse abdominal pain and bloating. Physical examination, ultrasound, and magnetic resonance imaging revealed a right ovarian tumor that was histopathologically diagnosed as a poorly differentiated Sertoli-Leydig cell tumor with heterologous elements. Her alpha-fetoprotein serum level was undetectable after tumor resection. Sertoli-Leydig cell tumors are rare sex cord-stromal tumors that account for 0.5% of all ovarian neoplasms. Sertoli-Leydig cell tumors tend to be unilateral and occur in women under 30 years of age. Although they are the most common virilizing tumor of the ovary, about 60% are endocrine-inactive tumors. Elevated serum levels of alpha-fetoprotein are rarely associated with Sertoli-Leydig cell tumors, with only approximately 30 such cases previously reported in the literature. The differential diagnosis should include common alpha-fetoprotein-producing ovarian entities such as germ cell tumors, as well as other non-germ cell tumors that have been rarely reported to produce this tumor marker. PMID:25926909

  16. Gastrointestinal leiomyosarcoma in a pygmy sperm whale (Kogia breviceps).

    PubMed

    Leone, Angelique; Dark, Michael; Kondo, Hirotaka; Rotstein, David S; Kiupel, Matti; Walsh, Michael T; Erlacher-Reid, Claire; Gordon, Nadia; Conway, Julia A

    2013-09-01

    An adult male pygmy sperm whale (Kogia breviceps) was stranded within a tidal pool on Fernandina Beach on the north Florida Atlantic coast (USA) and expired soon after discovery. Necropsy findings included a small intestinal mass markedly expanding the intestinal wall and partially obstructing the lumen. This finding likely led to the malnutrition and ultimately the stranding of this whale. The differential diagnoses for the mass based on gross evaluation included a duodenal adenocarcinoma, leiomyoma/sarcoma, gastrointestinal stroma tumor, and benign/malignant peripheral nerve sheath tumor, previously referred to as neurofibromas or schwannomas. The mass was presumptively diagnosed as a leiomyosarcoma via routine histopathology and confirmed by immunoreactivity for desmin and smooth actin (SMA). KIT, a gene name for CD 117, was negative, excluding a gastrointestinal stromal tumor (GIST). Leiomyosarcomas have been reported within numerous wild and domestic species, although this is the first reported case of any neoplasm in a pygmy sperm whale (K. breviceps).

  17. A novel approach in the treatment of neuroendocrine gastrointestinal tumors: Additive antiproliferative effects of interferon-γ and meta-iodobenzylguanidine

    PubMed Central

    Höpfner, Michael; Sutter, Andreas P; Huether, Alexander; Ahnert-Hilger, Gudrun; Scherübl, Hans

    2004-01-01

    Background Therapeutic options to effectively inhibit growth and spread of neuroendocrine gastrointestinal tumors are still limited. As both meta-iodobenzylguanidine (MIBG) and interferon-γ (IFNγ) cause antineoplastic effects in neuroendocrine gastrointestinal tumor cells, we investigated the antiproliferative effects of the combination of IFNγ and non-radiolabeled MIBG in neuroendocrine gut STC-1 and pancreatic carcinoid BON tumor cells. Methods and results IFNγ receptors were expressed in both models. IFNγ dose- and time-dependently inhibited the growth of both STC-1 and of BON tumor cells with IC50-values of 95 ± 15 U/ml and 135 ± 10 U/ml, respectively. Above 10 U/ml IFNγ induced apoptosis-specific caspase-3 activity in a time-dependent manner in either cell line and caused a dose-dependent arrest in the S-phase of the cell cycle. Furthermore, IFNγ induced cytotoxic effects in NE tumor cells. The NE tumor-targeted drug MIBG is selectively taken up via norepinephrine transporters, thereby specifically inhibiting growth in NE tumor cells. Intriguingly, IFNγ treatment induced an upregulation of norepinephrine transporter expression in neuroendocrine tumors cells, as determined by semi-quantitative RT-PCR. Co-application of sub-IC50 concentrations of IFNγ and MIBG led to additive growth inhibitory effects, which were mainly due to increased cytotoxicity and S-phase arrest of the cell cycle. Conclusion Our data show that IFNγ exerts antiproliferative effects on neuroendocrine gastrointestinal tumor cells by inducing cell cycle arrest, apoptosis and cytotoxicity. The combination of IFNγ with the NE tumor-targeted agent MIBG leads to effective growth control at reduced doses of either drug. Thus, the administration of IFNγ alone and more so, in combination with MIBG, is a promising novel approach in the treatment of neuroendocrine gastrointestinal tumors. PMID:15154969

  18. [Endocrine tumors of the gastrointestinal and pancreatic systems. Multiple endocrine adenoma from another viewpoint].

    PubMed

    Klempa, I; Helmstädter, V; Feurle, G; Röttger, P

    1980-05-01

    The 24 endocrine pancreatic tumors and 14 carcinoids were examined immunohistochemically for cholecystokinin, insulin, gastrin, GIP, glucagon, sercretin, VIP, motilin, neurotensin, pancreatic polypeptide (PP), somatostatin, and ACTH. In 12 tumors of the pancreas more than one peptide-containing cell type was observed. The clinical symptoms showed hypersecretion of only one of the hormones, however. The midgut carcinoids (jejunum, appendix) represented the classical view of the carcinoid as an argentaffin cell tumor secreting 5-hydroxytryptamine. Tumors originating in the foregut (bronchus, stomach, duodenum) and hindgut carcinoids (rectum) were nonargentaffine, containing and secreting various polypeptide hormones. We conclude that light microscopic immunohistochemical methods are useful in distinguishing endocrine from nonendocrine tumors and multihormonal syndromes (MEA) in the classification of predominant hormone-secreting tumors.

  19. Evaluation of dexmedetomidine in combination with sufentanil or butorphanol for postoperative analgesia in patients undergoing laparoscopic resection of gastrointestinal tumors

    PubMed Central

    Zhang, Xue-Kang; Chen, Qiu-Hong; Wang, Wen-Xiang; Hu, Qian

    2016-01-01

    Abstract The aim of this study was to evaluate the efficacy of dexmedetomidine in combination with sufentanil or butorphanol for postoperative analgesia in patients undergoing laparoscopic resection of a gastrointestinal tumor. This quasi-experimental trial was conducted in Nanchang, China, from January 2014 to December 2015. Eighty patients (age 27–70 years, American Society of Anesthesiologists physical status I–II) undergoing laparoscopic resection of a gastrointestinal tumor were randomized into 4 groups and offered intravenous patient-controlled analgesia for pain control after surgery. The patients received sufentanil 2.0 μg/kg in combination with dexmedetomidine 1.5 μg/kg (group S1) or 2.0 μg/kg (group S2), or butorphanol 0.15 mg/kg in combination with dexmedetomidine 1.5 0 μg/kg (group N1) or 2.0 μg/kg (group N2). Oxygen saturation, mean arterial pressure (MAP), heart rate, visual analog scale score, and Ramsay sedation score were recorded at enrollment (T0), at extubation (T1), and 4 (T2), 8 (T3), 12 (T4), 24 (T5), and 48 (T6) hours thereafter. Side effects and satisfaction scores were evaluated after surgery. MAP increased in all groups at T1 but not significantly so when compared with T0. Heart rate decreased significantly in group S2 when compared with the other groups at T1–T5 (P < 0.05). MAP decreased significantly in group S2 when compared with group S1 at T4–T6 (P < 0.05). MAP increased significantly in group N1 when compared with group N2 at T4–T5 (P < 0.05). There was a statistically significant decrease in mean visual analog scale score in group S2 when compared with group S1 at T2 (P < 0.05) and group N2 at T1–T2 (P < 0.05). Two patients in group S1 had vomiting. There were no reports of drowsiness, respiratory depression, or other complications. The satisfaction score was higher in group S2 than in the other groups. Dexmedetomidine in combination with sufentanil or butorphanol can be used safely

  20. Human tumors instigate granulin-expressing hematopoietic cells that promote malignancy by activating stromal fibroblasts in mice

    PubMed Central

    Elkabets, Moshe; Gifford, Ann M.; Scheel, Christina; Nilsson, Bjorn; Reinhardt, Ferenc; Bray, Mark-Anthony; Carpenter, Anne E.; Jirström, Karin; Magnusson, Kristina; Ebert, Benjamin L.; Pontén, Fredrik; Weinberg, Robert A.; McAllister, Sandra S.

    2011-01-01

    Systemic instigation is a process by which endocrine signals sent from certain tumors (instigators) stimulate BM cells (BMCs), which are mobilized into the circulation and subsequently foster the growth of otherwise indolent carcinoma cells (responders) residing at distant anatomical sites. The identity of the BMCs and their specific contribution or contributions to responder tumor growth have been elusive. Here, we have demonstrated that Sca1+cKit– hematopoietic BMCs of mouse hosts bearing instigating tumors promote the growth of responding tumors that form with a myofibroblast-rich, desmoplastic stroma. Such stroma is almost always observed in malignant human adenocarcinomas and is an indicator of poor prognosis. We then identified granulin (GRN) as the most upregulated gene in instigating Sca1+cKit– BMCs relative to counterpart control cells. The GRN+ BMCs that were recruited to the responding tumors induced resident tissue fibroblasts to express genes that promoted malignant tumor progression; indeed, treatment with recombinant GRN alone was sufficient to promote desmoplastic responding tumor growth. Further, analysis of tumor tissues from a cohort of breast cancer patients revealed that high GRN expression correlated with the most aggressive triple-negative, basal-like tumor subtype and reduced patient survival. Our data suggest that GRN and the unique hematopoietic BMCs that produce it might serve as novel therapeutic targets. PMID:21266779

  1. Evidence for a stromal-epithelial "lactate shuttle" in human tumors: MCT4 is a marker of oxidative stress in cancer-associated fibroblasts.

    PubMed

    Whitaker-Menezes, Diana; Martinez-Outschoorn, Ubaldo E; Lin, Zhao; Ertel, Adam; Flomenberg, Neal; Witkiewicz, Agnieszka K; Birbe, Ruth C; Howell, Anthony; Pavlides, Stephanos; Gandara, Ricardo; Pestell, Richard G; Sotgia, Federica; Philp, Nancy J; Lisanti, Michael P

    2011-06-01

    Recently, we proposed a new mechanism for understanding the Warburg effect in cancer metabolism. In this new paradigm, cancer-associated fibroblasts undergo aerobic glycolysis, and extrude lactate to "feed" adjacent cancer cells, which then drives mitochondrial biogenesis and oxidative mitochondrial metabolism in cancer cells. Thus, there is vectorial transport of energy-rich substrates from the fibroblastic tumor stroma to anabolic cancer cells. A prediction of this hypothesis is that cancer-associated fibroblasts should express MCT4, a mono-carboxylate transporter that has been implicated in lactate efflux from glycolytic muscle fibers and astrocytes in the brain. To address this issue, we co-cultured MCF7 breast cancer cells with normal fibroblasts. Interestingly, our results directly show that breast cancer cells specifically induce the expression of MCT4 in cancer-associated fibroblasts; MCF7 cells alone and fibroblasts alone, both failed to express MCT4. We also show that the expression of MCT4 in cancer-associated fibroblasts is due to oxidative stress, and can be prevented by pre-treatment with the anti-oxidant N-acetyl-cysteine. In contrast to our results with MCT4, we see that MCT1, a transporter involved in lactate uptake, is specifically upregulated in MCF7 breast cancer cells when co-cultured with fibroblasts. Virtually identical results were also obtained with primary human breast cancer samples. In human breast cancers, MCT4 selectively labels the tumor stroma, e.g., the cancer-associated fibroblast compartment. Conversely, MCT1 was selectively expressed in the epithelial cancer cells within the same tumors. Functionally, we show that overexpression of MCT4 in fibroblasts protects both MCF7 cancer cells and fibroblasts against cell death, under co-culture conditions. Thus, we provide the first evidence for the existence of a stromal-epithelial lactate shuttle in human tumors, analogous to the lactate shuttles that are essential for the normal

  2. 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.

    PubMed

    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.

  3. Hepatic Arterial Chemoembolization Using Drug-Eluting Beads in Gastrointestinal Neuroendocrine Tumor Metastatic to the Liver

    SciTech Connect

    Gaur, Shantanu K.; Friese, Jeremy L.; Sadow, Cheryl A.; Ayyagari, Rajasekhara; Binkert, Christoph A.; Schenker, Matthew P.; Kulke, Matthew; Baum, Richard

    2011-06-15

    Purpose: This study was designed to evaluate short (<3 months) and intermediate-term (>3 months) follow-up in patients with metastatic neuroendocrine tumor to the liver who underwent hepatic arterial chemoembolization with drug-eluting beads at a single institution. Methods: Institutional review board approval was obtained for this retrospective review. All patients who were treated with 100-300 or 300-500 {mu}m drug-eluting LC Beads (Biocompatibles, UK) preloaded with doxorubicin (range, 50-100 mg) for GI neuroendocrine tumor metastatic to the liver from June 2004 to June 2009 were included. CT and MRI were evaluated for progression using Response Evaluation Criteria In Solid Tumors (RECIST) or European Association for the Study of the Liver (EASL) criteria. Short-term (<3 months) and intermediate-term (>3 months) imaging response was determined and Kaplan-Meier survival curves were plotted. Results: Thirty-eight drug-eluting bead chemoembolization procedures were performed on 32 hepatic lobes, comprising 21 treatment cycles in 18 patients. All procedures were technically successful with two major complications (biliary injuries). At short-term follow-up (<3 months), 22 of 38 (58%) procedures and 10 of 21 (48%) treatment cycles produced an objective response (OR) with the remainder having stable disease (SD). At intermediate-term follow-up (mean, 445 days; range, 163-1247), 17 of 26 (65%) procedures and 8 of 14 (57%) treatment cycles produced an OR. Probability of progressing was approximately 52% at 1 year with a median time to progression of 419 days. Conclusions: Drug-eluting bead chemoembolization is a reasonable alternative to hepatic arterial embolization and chemoembolization for the treatment of metastatic neuroendocrine tumor to the liver.

  4. Update in Cancer Chemotherapy: Gastrointestinal Cancer, Cancer of the Stomach and Carcinoid Tumors

    PubMed Central

    Wright, Jane C.

    1986-01-01

    Cancer chemotherapy in the treatment of advanced gastric cancer provides only palliation with perhaps increased survival time in some patients. The primary treatment of gastric carcinomas is surgical, as this is the only hope for cure. It is estimated that 80 to 85 percent of patients with newly diagnosed cases of stomach cancer will be dead of their disease within five years. Radiation therapy alone is seldom employed, except as a palliative measure to control hemorrhage or pain. There are no data to suggest that postoperative radiation increases survival rates. Single-agent chemotherapy is of temporary palliative value in 20 to 30 percent of cases with a duration of response from three to five months. Combination chemotherapy has shown a somewhat higher response rate than single-agent therapy. In advanced gastric cancer, there is no evidence of improved long-term disease-free survival rates with any combination yet reported. The treatment of carcinoid cancer of the intestinal tract is surgical removal, as this offers the only hope of cure. Radiation therapy is of little benefit, except for moderate palliation in cases of extensive liver metasasis. Carcinoid cancers are moderately sensitive to chemotherapy. While some adjuvant chemotherapy trials suggest improvement, major survival gains remain to be demonstrated. Uncertainty as to the role of chemotherapy in the treatment of gastrointestinal cancers is probably due to lack of data. PMID:3528508

  5. Mesenchymal stromal cells expressing ErbB-2/neu elicit protective antibreast tumor immunity in vivo, which is paradoxically suppressed by IFN-gamma and tumor necrosis factor-alpha priming.

    PubMed

    Romieu-Mourez, Raphaëlle; François, Moïra; Abate, Amanda; Boivin, Marie-Noëlle; Birman, Elena; Bailey, Dana; Bramson, Jonathan L; Forner, Kathy; Young, Yoon-Kow; Medin, Jeffrey A; Galipeau, Jacques

    2010-10-15

    It is unknown whether mesenchymal stromal cells (MSC) can regulate immune responses targeting tumor autoantigens of low immunogenicity. We tested here whether immunization with MSC could break immune tolerance towards the ErbB-2/HER-2/neu tumor antigen and the effects of priming with IFN-γ and tumor necrosis factor-α (TNF-α) on this process. BALB/c- and C57BL/6-derived MSC were lentivirally transduced to express a kinase-inactive rat neu mutant (MSC/Neu). Immunization of BALB/c mice with nontreated or IFN-γ-primed allogeneic or syngeneic MSC/Neu induced similar levels of anti-neu antibody titers; however, only syngeneic MSC/Neu induced protective neu-specific CD8(+) T cell responses. Compared to immunization with nontreated or IFN-γ-primed syngeneic MSC/Neu, the number of circulating neu-specific CD8(+) T cells and titers of anti-neu antibodies were observed to be decreased after immunizations with IFN-γ- plus TNF-α-primed MSC/Neu. In addition, syngeneic MSC/Neu seemed more efficient than IFN-γ-primed MSC/Neu at inducing a protective therapeutic antitumor immune response resulting in the regression of transplanted neu-expressing mammary tumor cells. In vitro antigen-presenting cell assays performed with paraformaldehyde-fixed or live MSC showed that priming with IFN-γ plus TNF-α, compared to priming with IFN-γ alone, increased antigen presentation as well as the production of immunosuppressive factors. These data suggest that whereas MSC could effectively serve as antigen-presenting cells to induce immune responses aimed at tumor autoantigens, these functions are critically regulated by IFN-γ and TNF-α.

  6. Expression Analyses Revealed Thymic Stromal Co-Transporter/Slc46A2 Is in Stem Cell Populations and Is a Putative Tumor Suppressor.

    PubMed

    Kim, Ki Yeon; Lee, Gwanghee; Yoon, Minsang; Cho, Eun Hye; Park, Chan-Sik; Kim, Moon Gyo

    2015-06-01

    By combining conventional single cell analysis with flow cytometry and public database searches with bioinformatics tools, we extended the expression profiling of thymic stromal cotransporter (TSCOT), Slc46A2/Ly110, that was shown to be expressed in bipotent precursor and cortical thymic epithelial cells. Genome scale analysis verified TSCOT expression in thymic tissue- and cell type- specific fashion and is also expressed in some other epithelial tissues including skin and lung. Coexpression profiling with genes, Foxn1 and Hoxa3, revealed the role of TSCOT during the organogenesis. TSCOT expression was detected in all thymic epithelial cells (TECs), but not in the CD31(+) endothelial cell lineage in fetal thymus. In addition, ABC transporter-dependent side population and Sca-1(+) fetal TEC populations both contain TSCOT-expressing cells, indicating TEC stem cells express TSCOT. TSCOT expression was identified as early as in differentiating embryonic stem cells. TSCOT expression is not under the control of Foxn1 since TSCOT is present in the thymic rudiment of nude mice. By searching variations in the expression levels, TSCOT is positively associated with Grhl3 and Irf6. Cytokines such as IL1b, IL22 and IL24 are the potential regulators of the TSCOT expression. Surprisingly, we found TSCOT expression in the lung is diminished in lung cancers, suggesting TSCOT may be involved in the suppression of lung tumor development. Based on these results, a model for TEC differentiation from the stem cells was proposed in context of multiple epithelial organ formation.

  7. Hyaluronan synthase HAS2 promotes tumor progression in bone by stimulating the interaction of breast cancer stem-like cells with macrophages and stromal cells

    PubMed Central

    Okuda, Hiroshi; Kobayashi, Aya; Xia, Bo; Watabe, Misako; Pai, Sudha K; Hirota, Shigeru; Xing, Fei; Liu, Wen; Pandey, Puspa R; Fukuda, Koji; Modur, Vishnu; Ghosh, Arnab; Wilber, Andrew; Watabe, Kounosuke

    2012-01-01

    The molecular mechanisms that operate within the organ microenvironment to support metastatic progression remain unclear. Here we report that upregulation of the hyaluronan synthase HAS2 occurs in highly metastatic breast stem-like cancer cells (CSCs) defined by CD44+/CD24−/ESA+ phenotype, where it plays a critical role in the generation of a pro-metastatic microenvironment in breast cancer. HAS2 was critical for interaction of CSCs with tumor associated macrophages (TAMs), leading to enhanced secretion of PDGF-BB from TAMs which then activated stromal cells and enhanced CSC self-renewal. Loss of HAS2 in CSCs or treatment with 4-methylumbelliferone (4-MU), an inhibitor of hyaluronan synthases which blocks hyaluronan production, drastically reduced the incidence and growth of metastatic lesions in vitro or in vivo, respectively. Taken together, our findings demonstrate a critical role for HAS2 in the development of a pro-metastatic microenvironment and suggest that HAS2 inhibitors can act as anti-metastatic agents that disrupt a paracrine growth factor loop within this microenvironment. PMID:22113945

  8. Cyclooxygenase-2 or tumor necrosis factor-α inhibitors attenuate the mechanotransductive effects of pulsed focused ultrasound to suppress mesenchymal stromal cell homing to healthy and dystrophic muscle.

    PubMed

    Tebebi, Pamela A; Burks, Scott R; Kim, Saejeong J; Williams, Rashida A; Nguyen, Ben A; Venkatesh, Priyanka; Frenkel, Victor; Frank, Joseph A

    2015-04-01

    Maximal homing of infused stem cells to diseased tissue is critical for regenerative medicine. Pulsed focused ultrasound (pFUS) is a clinically relevant platform to direct stem cell migration. Through mechanotransduction, pFUS establishes local gradients of cytokines, chemokines, trophic factors (CCTF) and cell adhesion molecules (CAM) in treated skeletal muscle that subsequently infused mesenchymal stromal cells (MSC) can capitalize to migrate into the parenchyma. Characterizing molecular responses to mechanical pFUS effects revealed tumor necrosis factor-alpha (TNFα) drives cyclooxygenase-2 (COX2) signaling to locally increase CCTF/CAM that are necessary for MSC homing. pFUS failed to increase chemoattractants and induce MSC homing to treated muscle in mice pretreated with ibuprofen (nonspecific COX inhibitor) or etanercept (TNFα inhibitor). pFUS-induced MSC homing was also suppressed in COX2-knockout mice, demonstrating ibuprofen blocked the mechanically induced CCTF/CAM by acting on COX2. Anti-inflammatory drugs, including ibuprofen, are administered to muscular dystrophy (MD) patients, and ibuprofen also suppressed pFUS-induced homing to muscle in a mouse model of MD. Drug interactions with cell therapies remain unexplored and are not controlled for during clinical cell therapy trials. This study highlights potentially negative drug-host interactions that suppress stem cell homing and could undermine cell-based approaches for regenerative medicine.

  9. Prevalence of upper gastrointestinal symptoms and their influence on nutritional state and performance status in patients with different primary tumors receiving palliative care.

    PubMed

    Bovio, Giacomo; Fonte, Maria Luisa; Baiardi, Paola

    2014-02-01

    The aim of this study was to investigate the relationship between gastrointestinal symptoms, nutritional balance, and performance status in patients receiving palliative care for advanced cancers originating in different sites. We studied a total of 105 patients. Upper gastrointestinal symptoms, Eastern Cooperative Oncology Group Performance Status score (ECOG-PS), dietary intakes, anthropometric measures, and some serum proteins were determined. Unintentional weight loss, alterations in anthropometric measures, and highest number of symptoms were greater in patients with lung and stomach cancer. No differences were found in ECOG-PS according to cancer site. Patients with gastric or lung cancer have most evidence of protein-calorie malnutrition and a higher prevalence of upper gastrointestinal symptoms. The performance status is not affected by tumor site. Early nutritional support should be planned for all patients with cancer, especially for patients with gastric or lung cancer.

  10. Gastrointestinal complications of von Recklinghausen's disease: two case reports and a review of the literature.

    PubMed

    Pinsk, I; Dukhno, O; Ovnat, A; Levy, I

    2003-12-01

    There are few reports of the association between neurofibromatosis (von Recklinghausen's disease) and large, solid stromal tumours of the gastrointestinal tract. The prevalence of gastrointestinal involvement in von Recklinghausen's disease has been estimated at 11%-25%. Some associated gastrointestinal stromal tumours present clinically as bowel obstruction, perforation or gastrointestinal bleeding. We recently treated two patients with this condition who presented with gastrointestinal bleeding and were diagnosed with gastrointestinal stromal tumours. We report the unique aspects of these cases and discuss the diagnostic and management problems that are posed by this unusual association.

  11. Activation of the A2B adenosine receptor in B16 melanomas induces CXCL12 expression in FAP-positive tumor stromal cells, enhancing tumor progression

    PubMed Central

    Sorrentino, Claudia; Miele, Lucio; Porta, Amalia; Pinto, Aldo; Morello, Silvana

    2016-01-01

    The A2B receptor (A2BR) can mediate adenosine-induced tumor proliferation, immunosuppression and angiogenesis. Targeting the A2BR has proved to be therapeutically effective in some murine tumor models, but the mechanisms of these effects are still incompletely understood. Here, we report that pharmacologic inhibition of A2BR with PSB1115, which inhibits tumor growth, decreased the number of fibroblast activation protein (FAP)-expressing cells in tumors in a mouse model of melanoma. This effect was associated with reduced expression of fibroblast growth factor (FGF)-2. Treatment of melanoma-associated fibroblasts with the A2BR agonist Bay60-6583 enhanced CXCL12 and FGF2 expression. This effect was abrogated by PSB1115. The A2AR agonist CGS21680 did not induce CXCL12 or FGF2 expression in tumor associated fibroblasts. Similar results were obtained under hypoxic conditions in skin-derived fibroblasts, which responded to Bay60-6583 in an A2BR-dependent manner, by stimulating pERK1/2. FGF2 produced by Bay60-6583-treated fibroblasts directly enhanced the proliferation of melanoma cells. This effect could be reversed by PSB1115 or an anti-FGF2 antibody. Interestingly, melanoma growth in mice receiving Bay60-6583 was attenuated by inhibition of the CXCL12/CXCR4 pathway with AMD3100. CXCL12 and its receptor CXCR4 are involved in angiogenesis and immune-suppression. Treatment of mice with AMD3100 reduced the number of CD31+ cells induced by Bay60-6583. Conversely, CXCR4 blockade did not affect the accumulation of tumor-infiltrating MDSCs or Tregs. Together, our data reveal an important role for A2BR in stimulating FGF2 and CXCL12 expression in melanoma-associated fibroblasts. These factors contribute to create a tumor-promoting microenvironment. Our findings support the therapeutic potential of PSB1115 for melanoma. PMID:27590504

  12. Stromal genes discriminate preinvasive from invasive disease, predict outcome, and highlight inflammatory pathways in digestive cancers

    PubMed Central

    Saadi, Amel; Shannon, Nicholas B.; Lao-Sirieix, Pierre; O’Donovan, Maria; Walker, Elaine; Clemons, Nicholas J.; Hardwick, James S.; Zhang, Chunsheng; Das, Madhumita; Save, Vicki; Novelli, Marco; Balkwill, Frances; Fitzgerald, Rebecca C.

    2010-01-01

    The stromal compartment is increasingly recognized to play a role in cancer. However, its role in the transition from preinvasive to invasive disease is unknown. Most gastrointestinal tumors have clearly defined premalignant stages, and Barrett’s esophagus (BE) is an ideal research model. Supervised clustering of gene expression profiles from microdissected stroma identified a gene signature that could distinguish between BE metaplasia, dysplasia, and esophageal adenocarcinoma (EAC). EAC patients overexpressing any of the five genes (TMEPAI, JMY, TSP1, FAPα, and BCL6) identified from this stromal signature had a significantly poorer outcome. Gene ontology analysis identified a strong inflammatory component in BE disease progression, and key pathways included cytokine–cytokine receptor interactions and TGF-β. Increased protein levels of inflammatory-related genes significantly up-regulated in EAC compared with preinvasive stages were confirmed in the stroma of independent samples, and in vitro assays confirmed functional relevance of these genes. Gene set enrichment analysis of external datasets demonstrated that the stromal signature was also relevant in the preinvasive to invasive transition of the stomach, colon, and pancreas. These data implicate inflammatory pathways in the genesis of gastrointestinal tract cancers, which can affect prognosis. PMID:20080664

  13. Sorafenib Tosylate in Treating Patients With Progressive Metastatic Neuroendocrine Tumors

    ClinicalTrials.gov

    2014-11-14

    Gastrinoma; Glucagonoma; Insulinoma; Metastatic Gastrointestinal Carcinoid Tumor; Neuroendocrine Tumor; Pancreatic Polypeptide Tumor; Recurrent Gastrointestinal Carcinoid Tumor; Recurrent Islet Cell Carcinoma; Somatostatinoma; WDHA Syndrome

  14. Radiotherapy combined with TLR7/8 activation induces strong immune responses against gastrointestinal tumors

    PubMed Central

    Tietz, Alexandra; Rahbari, Nuh N.; Bork, Ulrich; Schmidt, Thomas; Kahlert, Christoph; Haberkorn, Uwe; Tomai, Mark A.; Lipson, Kenneth E.; Carretero, Rafael; Weitz, Jürgen; Koch, Moritz; Huber, Peter E.

    2015-01-01

    In addition to local cytotoxic activity, radiotherapy may also elicit local and systemic antitumor immunity, which may be augmented by immunotherapeutic agents including Toll-like receptor (TLR) 7/8 agonists. Here, we investigated the ability of 3M-011 (854A), a TLR7/8 agonist, to boost the antigen-presenting activity of dendritic cells (DC) as an adjuvant to radiotherapy. The combined treatment induced marked local and systemic responses in subcutaneous and orthotopic mouse models of colorectal and pancreatic cancer. In vitro cytotoxicity assays as well as in vivo depletion experiments with monoclonal antibodies identified NK and CD8 T cells as the cell populations mediating the cytotoxic effects of the treatment, while in vivo depletion of CD11c+ dendritic cells (DC) in CD11c-DTR transgenic mice revealed DC as the pivotal immune hub in this setting. The specificity of the immune reaction was confirmed by ELISPOT assays. TLR7/8 agonists therefore seem to be potent adjuvants to radiotherapy, inducing strong local and profound systemic immune responses to tumor antigens released by conventional therapy. PMID:25609199

  15. The functional interplay between EGFR overexpression, hTERT activation, and p53 mutation in esophageal epithelial cells with activation of stromal fibroblasts induces tumor development, invasion, and differentiation.

    PubMed

    Okawa, Takaomi; Michaylira, Carmen Z; Kalabis, Jiri; Stairs, Douglas B; Nakagawa, Hiroshi; Andl, Claudia D; Johnstone, Cameron N; Klein-Szanto, Andres J; El-Deiry, Wafik S; Cukierman, Edna; Herlyn, Meenhard; Rustgi, Anil K

    2007-11-01

    Esophageal cancer is a prototypic squamous cell cancer that carries a poor prognosis, primarily due to presentation at advanced stages. We used human esophageal epithelial cells as a platform to recapitulate esophageal squamous cell cancer, thereby providing insights into the molecular pathogenesis of squamous cell cancers in general. This was achieved through the retroviral-mediated transduction into normal, primary human esophageal epithelial cells of epidermal growth factor receptor (EGFR), the catalytic subunit of human telomerase (hTERT), and p53(R175H), genes that are frequently altered in human esophageal squamous cell cancer. These cells demonstrated increased migration and invasion when compared with control cells. When these genetically altered cells were placed within the in vivo-like context of an organotypic three-dimensional (3D) culture system, the cells formed a high-grade dysplastic epithelium with malignant cells invading into the stromal extracellular matrix (ECM). The invasive phenotype was in part modulated by the activation of matrix metalloproteinase-9 (MMP-9). Using pharmacological and genetic approaches to decrease MMP-9, invasion into the underlying ECM could be suppressed partially. In addition, tumor differentiation was influenced by the type of fibroblasts within the stromal ECM. To that end, fetal esophageal fibroblasts fostered a microenvironment conducive to poorly differentiated invading tumor cells, whereas fetal skin fibroblasts supported a well-differentiated tumor as illustrated by keratin "pearl" formation, a hallmark feature of well-differentiated squamous cell cancers. When inducible AKT was introduced into fetal skin esophageal fibroblasts, a more invasive, less-differentiated esophageal cancer phenotype was achieved. Invasion into the stromal ECM was attenuated by genetic knockdown of AKT1 as well as AKT2. Taken together, alterations in key oncogenes and tumor suppressor genes in esophageal epithelial cells, the composition

  16. Resveratrol as a natural anti-tumor necrosis factor-α molecule: implications to dendritic cells and their crosstalk with mesenchymal stromal cells.

    PubMed

    Silva, Andreia M; Oliveira, Marta I; Sette, Laura; Almeida, Catarina R; Oliveira, Maria J; Barbosa, Mário A; Santos, Susana G

    2014-01-01

    Dendritic cells (DC) are promising targets for inducing tolerance in inflammatory conditions. Thus, this study aims to investigate the effects of the natural anti-inflammatory molecule resveratrol on human DC at phenotypic and functional levels, including their capacity to recruit mesenchymal stem/stromal cells (MSC). Primary human monocyte-derived DC and bone marrow MSC were used. DC immunophenotyping revealed that small doses of resveratrol (10 µM) reduce cell activation in response to tumor necrosis factor (TNF)-α, significantly decreasing surface expression of CD83 and CD86. Functionally, IL-12/IL-23 secretion induced by TNF-α was significantly reduced by resveratrol, while IL-10 levels increased. Resveratrol also inhibited T cell proliferation, in response to TNF-α-stimulated DC. The underlying mechanism was investigated by Western blot and imaging flow cytometry (ImageStreamX), and likely involves impairment of nuclear translocation of the p65 NF-κB subunit. Importantly, results obtained demonstrate that DC are able to recruit MSC through extracellular matrix components, and that TNF-α impairs DC-mediated recruitment. Matrix metalloproteinases (MMP) produced by both cell populations were visualized by gelatin zymography. Finally, time-lapse microscopy analysis revealed a significant decrease on DC and MSC motility in co-cultures, indicating cell interaction, and TNF-α further decreased MSC motility, while resveratrol recovered it. Thus, the current study points out the potential of resveratrol as a natural anti-TNF-α drug, capable of modulating DC phenotype and function, as well as DC-mediated MSC recruitment.

  17. Histopathology and enhanced detection of tumor invasion of peritoneal membranes.

    PubMed

    Chen, Jey-Hsin; Borges, Melissa

    2017-01-01

    Tumor invasion of the peritoneal membrane may have an adverse prognostic significance, but its histopathologic features can be diagnostically difficult to recognize. We observed that local peritoneal injury associated with tumor invasion is characterized by activation and proliferation of serosal stromal cells that express cytokeratin, a characteristic property of injured serosal membranes that may have diagnostic utility. To explore this, we examined 120 primary tumors of the gastrointestinal tract and pancreaticobiliary system using cytokeratin and elastic stains to assess for tumor invasion of peritoneal membranes. Peritoneal invasion by tumor was associated with retraction, splaying, and destruction of the elastic lamina and proliferation of keratin-expressing stromal cells of serosal membranes. All 82 peritoneal invasive tumors were characterized by neoplastic cells that invaded the elastic lamina and the serosal connective tissue with neoplastic cells that abutted or were surrounded by keratin-positive stromal cells, whereas all 38 tumors limited to the subserosa showed none of these features. The diagnosis of tumor invasion of peritoneal membranes is enhanced by the combined use of cytokeratin and elastic stains, which in turn would enable better histopathologic correlation with patient treatment and outcome.

  18. Histopathology and enhanced detection of tumor invasion of peritoneal membranes

    PubMed Central

    Borges, Melissa

    2017-01-01

    Tumor invasion of the peritoneal membrane may have an adverse prognostic significance, but its histopathologic features can be diagnostically difficult to recognize. We observed that local peritoneal injury associated with tumor invasion is characterized by activation and proliferation of serosal stromal cells that express cytokeratin, a characteristic property of injured serosal membranes that may have diagnostic utility. To explore this, we examined 120 primary tumors of the gastrointestinal tract and pancreaticobiliary system using cytokeratin and elastic stains to assess for tumor invasion of peritoneal membranes. Peritoneal invasion by tumor was associated with retraction, splaying, and destruction of the elastic lamina and proliferation of keratin-expressing stromal cells of serosal membranes. All 82 peritoneal invasive tumors were characterized by neoplastic cells that invaded the elastic lamina and the serosal connective tissue with neoplastic cells that abutted or were surrounded by keratin-positive stromal cells, whereas all 38 tumors limited to the subserosa showed none of these features. The diagnosis of tumor invasion of peritoneal membranes is enhanced by the combined use of cytokeratin and elastic stains, which in turn would enable better histopathologic correlation with patient treatment and outcome. PMID:28282462

  19. Grp94 in complexes with IgG is a soluble diagnostic marker of gastrointestinal tumors and displays immune-stimulating activity on peripheral blood immune cells

    PubMed Central

    Tramentozzi, Elisa; Ruli, Erlis; Angriman, Imerio; Bardini, Romeo; Campora, Michela; Guzzardo, Vincenza; Zamarchi, Rita; Rossi, Elisabetta; Rugge, Massimo; Finotti, Paola

    2016-01-01

    Glucose-regulated protein94 (Grp94), the most represented endoplasmic reticulum (ER)-resident heat shock protein (HSP), is a tumor antigen shared by different types of solid and hematological tumors. The tumor-specific feature of Grp94 is its translocation from the ER to the cell surface where it displays pro-oncogenic functions. This un-physiological location has important implications for both the tumor pathology and anti-tumor therapy. We wanted to address the question of whether Grp94 could be measured as liquid marker in cancer patients in order to make predictions of diagnostic and therapeutic relevance for the tumor. To this aim, we performed an in-depth investigation on patients with primary tumors of the gastrointestinal (GI) tract, using different methodological approaches to detect Grp94 in tumor tissues, plasma and peripheral blood mononuclear cells (PBMCs). Results indicate that Grp94 is not only the antigen highly expressed in any tumor tissue and in cells of tumor infiltrates, mostly B lymphocytes, but it is also found in the circulation. However, the only form in which Grp94 was detected in the plasma of any patients and in B lymphocytes induced to proliferate, was that of stable complexes with Immunoglobulin (Ig)G. Using a specific immune-enzyme assay to measure plasma Grp94-IgG complexes, we showed that Grp94-IgG complexes were significantly increased in cancer patients compared to healthy control subjects, serving as diagnostic tumor biomarker. Results also demonstrate that the stimulation of patient PBMCs with Grp94-IgG complexes led to an increased secretion of inflammatory cytokines that might drive a potentially beneficial anti-tumor effect. PMID:27662661

  20. [The role of stromal mast cells in the modification of CD4+CD25+Foxp³ regulatory T cells, Th17 lymphocytes and cytotoxic lymphocytes Tc1 in the development and progression of tumor].

    PubMed

    Starska, Katarzyna; Brzezińska-Błaszczyk, Ewa

    2010-08-23

    Despite the lack of direct evidence that immune surveillance cells protect against tumor development, indirect clinical observations and experimental studies indicate activity in the immune response against cancer cells of various origin. Little is known about the effects of the stromal tumor mast cell (MC) in the activity of immune cells, i.e. CD4+CD25+Foxp³+ regulatory T cells, Th17 lymphocytes, cytotoxic lymphocytes Tc1 and their mutual modulatory function and regulation of the antitumor immune response. Factors synthesized by stromal tumor mast cells including histamine, COX-2, CXCL8 (IL-8), VEGF, IL-6, TNF, iNOS, MMP-8, and MMP-9 may, on the one hand, directly affect the activity of T lymphocyte subpopulations, i.e. iTreg, Tc1, and Th17, and thus regulate immunological processes occurring in the vicinity of the tumor. On the other hand, through effects on angiogenesis, apoptosis, the cell cycle, secretion of cytokines and the expression of adhesion molecules, they may indirectly determine the progression of the neoplasm. Understanding the regulatory mechanisms occurring in the system: tumor stroma mast cell → immune cells infiltrating the tumor (iTreg, Tc1, Th17 lymphocytes) → expression of factors involved in angiogenesis, apoptosis, the cell cycle, and secretion of cytokines and adhesion molecules creates the future possibility of influencing the activation and regulation of selected proneoplastic and antineoplastic factors appearing in the neoplasm environment. Research on these mechanisms may be the beginning of a new approach to the fight against cancer growth and provide an opportunity to introduce new methods of treatment. The aim of this study was to present the current knowledge on the role of stromal tumor CD117+ mast cells and factors secreted by these cells in the activation of T lymphocyte subpopulations, i.e. CD4+CD25+Foxp³+ regulatory T cells, Th17 lymphocytes, and cytotoxic lymphocytes Tc1, as well as to present their impact on the degree

  1. Is photodynamic therapy a selective treatment? Analysis of local complications after endoscopic photodynamic therapy of early stage tumors of gastrointestinal, tracheobronchial, and urinary tracts

    NASA Astrophysics Data System (ADS)

    Spinelli, Pasquale; Dal Fante, Marco; Mancini, Andrea

    1995-03-01

    Selectivity is the most emphasized advantage of photodynamic therapy (PDT). However, at drug and light doses used for clinical applications, response from normal tissue surrounding the tumor reduces the real selectivity of the drug-light system and increases the surface of the area responding to the treatment. It is now evident that light irradiation of a sensitized patient produces damage at a various degree not only in the tumor but also in non-neoplastic tissues included in the field of irradiation. We report our experience in endoscopic PDT of early stage tumors in tracheobronchial, gastrointestinal and urinary tracts, describing early and late local complications caused by the damage of normal tissues adjacent to the tumors and included in the field of light irradiation. Among 44 patients treated, local complications, attributable to a poor selectivity of the modality, occurred in 6 patients (14%). In particular, the rate of local complications was 9% in patients treated for esophageal tumors, 14% in patients with gastric tumors, 9% in patients with tracheobronchial tumors, and 67% in bladder cancer patients. Clinical pictures as well as endoscopic findings at various intervals from treatment showed that mucositis is a common event following endoscopic PDT. It causes exudation and significant tissue inflammatory response, whose consequences are different in the various organs treated. Photoradiation must be, as much as possible, limited to the malignant area.

  2. Intramural esophageal tumors

    PubMed Central

    Kozak, Katarzyna; Rębowski, Marek; Kozak, Józef

    2016-01-01

    Introduction Intramural esophageal tumors (IET) are located between unchanged mucous membrane and muscularis mucosae. They can be both benign and malignant. Aim To evaluate diagnostic and therapeutic difficulties of IET. Material and methods During the years 2010–2015, 11 patients with IET were treated in our clinic. Diagnostics included gastroscopy, computed tomography of the chest, endoscopic ultrasound (EUS) guided fine needle biopsy, and positron emission tomography (PET) of the esophagus in cases with no histopathological confirmation. Results Based on the conducted analysis we diagnosed 1 case of gastrointestinal stromal tumor (GIST), 1 case of adenocarcinoma, and 2 cases of esophageal cysts. In another 7 cases radiological images resembled leiomyoma but with no histopathological confirmation. Esophagectomy was performed in 2 cases of malignant tumors and 1 case of a large benign tumor. In other cases surgical enucleation of tumors was performed. Postoperatively we diagnosed 6 cases of leiomyoma, 1 case of schwannoma, 2 esophageal cysts, 1 case of GIST and 1 of esophageal cancer. Conclusions Intramural esophageal tumors is a very diverse group of tumors, both malignant and benign. In every case of IET we should seek histopathological conformation. Treatment of IET depends on localization, size and histopathological type of lesion. PMID:28096828

  3. GCP-2/CXCL6 synergizes with other endothelial cell-derived chemokines in neutrophil mobilization and is associated with angiogenesis in gastrointestinal tumors

    SciTech Connect

    Gijsbers, Klara; Gouwy, Mieke; Struyf, Sofie; Wuyts, Anja; Proost, Paul; Opdenakker, Ghislain; Penninckx, Freddy; Ectors, Nadine; Geboes, Karel; Van Damme, Jo . E-mail: jozef.vandamme@rega.kuleuven.ac.be

    2005-02-15

    The precise role of chemokines in neovascularization during inflammation or tumor growth is not yet fully understood. We show here that the chemokines granulocyte chemotactic protein-2 (GCP-2/CXCL6), interleukin-8 (IL-8/CXCL8), and monocyte chemotactic protein-1 (MCP-1/CCL2) are co-induced in microvascular endothelial cells after stimulation with pro-inflammatory stimuli. In contrast with its weak proliferative effect on endothelial cells, GCP-2 synergized with MCP-1 in neutrophil chemotaxis. This synergy may represent a mechanism for tumor development and metastasis by providing efficient leukocyte infiltration in the absence of exogenous immune modulators. To mimic endothelial cell-derived GCP-2 in vivo, GCP-2 was intravenously injected and shown to provoke a dose-dependent systemic response, composed of an immediate granulopenia, followed by a profound granulocytosis. By immunohistochemistry, GCP-2 was further shown to be expressed by endothelial cells from human patients with gastrointestinal (GI) malignancies. GCP-2 staining correlated with leukocyte infiltration into the tumor and with the expression of the matrix metalloproteinase-9 (MMP-9/gelatinase B). Together with previous findings, these data suggest that the production of GCP-2 by endothelial cells within the tumor can contribute to tumor development through neovascularization due to endothelial cell chemotaxis and to tumor cell invasion and metastasis by attracting and activating neutrophils loaded with proteases that promote matrix degradation.

  4. Superficial leiomyomas of the gastrointestinal tract with interstitial cells of Cajal

    PubMed Central

    Janevska, Vesna; Qerimi, Adelina; Basheska, Neli; Stojkova, Elena; Janevski, Vlado; Jovanovic, Rubens; Zhivadinovik, Julija; Spasevska, Liljana

    2015-01-01

    Objective: Some authors suggest common origin of gastrointestinal stromal tumors from stem cells, which may show diverse differentiation. There are reports in which cells morphologically identical to the interstitial cells of Cajal are found in deep leiomyomas. The aim of this study was to demonstrate CD117 positive cells in superficial gastrointestinal (GI) leiomyomas and to find other cells that would suggest diverse differentiation in histologically typical leiomyoma. Materials and methods: We analyzed 8 cases of superficial leiomyomas and one deep leiomyoma, received in our institutions as endoscopically or surgically obtained material. The tumor sections were immunohistochemicaly stained with CD117, CD34, NF, S100, αSMA, desmin, caldesmon and mast cell antigen. Results: All leiomyomas showed diffuse positivity for αSMA, caldesmon and desmin. All of them had CD117 and CD34 positive cells morphologically identical to the interstitial cells of Cajal between smooth muscle fibers, 5 had S-100 and NF positive cells and 2 showed positivity for GFAP. The cells were found in different quantity; they were usually diffusely scattered through the tumors without predilection site, forming small groups in some areas. Conclusion: CD177, CD34, S-100 and NF positive cells are present in superficial leiomyomas and they may suggest common origin of GI stromal tumors. PMID:26884872

  5. A rare case of metastatic germ cell tumor to stomach and duodenum masquerading as signet ring cell adenocarcinoma

    PubMed Central

    Sundaram, Sridhar; Patil, Prachi; Mehta, Shaesta; Ramadwar, Mukta

    2016-01-01

    Adenocarcinomas are the most common cancers affecting stomach. However gastrointestinal stromal tumors (GIST), lymphomas and neuroendocrine tumors (NETs) can also affect the stomach. But stomach is relatively rare site of involvement by metastasis. In this case report a rare metastasis of germ cell tumor (GCT) into stomach is described which clinically and endoscopically masquerade as primary gastric cancers. But detailed clinical examination and vigilant histopathological reporting proves the origin of tumor distant from stomach and thereby change the whole approach of management. PMID:27668229

  6. Endoscopic ultrasound-guided tissue sampling of small subepithelial tumors of the upper gastrointestinal tract with a 22-gauge core biopsy needle

    PubMed Central

    Schlag, Christoph; Menzel, Christoph; Götzberger, Manuela; Nennstiel, Simon; Klare, Peter; Wagenpfeil, Stefan; Schmid, Roland M.; Weirich, Gregor; von Delius, Stefan

    2017-01-01

    Background and study aims The optimal approach to small subepithelial tumors (SETs) of the upper gastrointestinal tract remains inconclusive. The aim of this study was to evaluate endoscopic ultrasound-guided fine needle biopsy (EUS-FNB) for less invasive tissue sampling of small SETs of the upper gastrointestinal tract. Patients and methods In this prospective observational study patients with small ( ≤ 3 cm) SETs of the upper gastrointestinal tract were eligible and underwent EUS-FNB with a 22-gauge core biopsy needle. The main outcome measure was the diagnostic yield. The number of obtained core biopsies was also assessed. Results Twenty patients were included. The mean SET size was 16 mm (range 10 – 27 mm). EUS-FNB was technically feasible in all cases and no complications were observed. The diagnostic yield was 75 %. Core biopsy specimens were obtained in only 25 % of cases. Conclusion EUS-FNB with a 22-gauge core biopsy needle of small SETs can achieve a definite diagnosis in the majority of cases. However, because core samples cannot regularly be obtained, EUS-FNB seems not to be convincingly superior to standard EUS-FNA in this setting PMID:28299351

  7. EF5 and Motexafin Lutetium in Detecting Tumor Cells in Patients With Abdominal or Non-Small Cell Lung Cancer

    ClinicalTrials.gov

    2013-01-15

    Advanced Adult Primary Liver Cancer; Carcinoma of the Appendix; Fallopian Tube Cancer; Gastrointestinal Stromal Tumor; Localized Extrahepatic Bile Duct Cancer; Localized Gallbladder Cancer; Localized Gastrointestinal Carcinoid Tumor; Localized Resectable Adult Primary Liver Cancer; Localized Unresectable Adult Primary Liver Cancer; Metastatic Gastrointestinal Carcinoid Tumor; Ovarian Sarcoma; Ovarian Stromal Cancer; Primary Peritoneal Cavity Cancer; Recurrent Adult Primary Liver Cancer; Recurrent Adult Soft Tissue Sarcoma; Recurrent Colon Cancer; Recurrent Extrahepatic Bile Duct Cancer; Recurrent Gallbladder Cancer; Recurrent Gastric Cancer; Recurrent Gastrointestinal Carcinoid Tumor; Recurrent Non-small Cell Lung Cancer; Recurrent Ovarian Epithelial Cancer; Recurrent Ovarian Germ Cell Tumor; Recurrent Pancreatic Cancer; Recurrent Rectal Cancer; Recurrent Small Intestine Cancer; Recurrent Uterine Sarcoma; Regional Gastrointestinal Carcinoid Tumor; Small Intestine Adenocarcinoma; Small Intestine Leiomyosarcoma; Small Intestine Lymphoma; Stage 0 Non-small Cell Lung Cancer; Stage I Adult Soft Tissue Sarcoma; Stage I Colon Cancer; Stage I Gastric Cancer; Stage I Non-small Cell Lung Cancer; Stage I Ovarian Epithelial Cancer; Stage I Ovarian Germ Cell Tumor; Stage I Pancreatic Cancer; Stage I Rectal Cancer; Stage I Uterine Sarcoma; Stage II Adult Soft Tissue Sarcoma; Stage II Colon Cancer; Stage II Gastric Cancer; Stage II Non-small Cell Lung Cancer; Stage II Ovarian Epithelial Cancer; Stage II Ovarian Germ Cell Tumor; Stage II Pancreatic Cancer; Stage II Rectal Cancer; Stage II Uterine Sarcoma; Stage III Adult Soft Tissue Sarcoma; Stage III Colon Cancer; Stage III Gastric Cancer; Stage III Ovarian Epithelial Cancer; Stage III Ovarian Germ Cell Tumor; Stage III Pancreatic Cancer; Stage III Rectal Cancer; Stage III Uterine Sarcoma; Stage IIIA Non-small Cell Lung Cancer; Stage IIIB Non-small Cell Lung Cancer; Stage IV Adult Soft Tissue Sarcoma; Stage IV Colon Cancer; Stage

  8. A multicenter phase II study of pazopanib in patients with advanced gastrointestinal stromal tumors (GIST) following failure of at least imatinib and sunitinib

    PubMed Central

    Ganjoo, K. N.; Villalobos, V. M.; Kamaya, A.; Fisher, G. A.; Butrynski, J. E.; Morgan, J. A.; Wagner, A. J.; D'Adamo, D.; McMillan, A.; Demetri, G. D.; George, S.

    2014-01-01

    Background Advanced GISTs are incurable, but often treatable for years with tyrosine kinase inhibitors (TKIs). The majority of GISTs harbor an oncogenic activating mutation in KIT or PDGFRA. Inhibition of this activating mutation with TKIs most often leads to durable disease control for many patients. However, almost all patients develop resistance to these TKIs, typically due to the development of secondary mutations, heralding the need for new therapeutic options. We conducted a phase II study evaluating the efficacy and toxicity of pazopanib, a broad spectrum TKI inhibiting KIT, VEGFRs (−1, −2, and −3), and PDGFR (-α and-β) in patients with advanced GIST following failure of at least imatinib and sunitinib. Methods Patients received pazopanib 800 mg orally once daily. All patients were assessed for efficacy with CT scans every 8 weeks (two cycles). Patients continued pazopanib until progression or unacceptable toxicity. The primary end point was the 24-week nonprogression [complete response+partial response+stable disease (SD)] rate (NPR) per RECIST 1.1. Secondary end points included PFS, OS, and toxicity. Results Between August 2011 and September 2012, a total of 25 patients were treated at two institutions. Median number of prior therapy was 3 (range 2–7). A total of 90 cycles of pazopanib were administered, with a median of two cycles (range 1 to 17+) per patient. Best response of SD at any time was observed in 12 (48%) patients. The NPR was 17% [95% confidence interval (CI) 4.5–37]. All but one patient discontinued protocol either due to PD (n = 19) or intolerance (n = 4). One patient with succinate dehydrogenase (SDH)-deficient GIST exhibited continuing disease control after 17 cycles. The median PFS for the entire cohort was 1.9 months (95% CI 1.6–5.2), and the median OS was 10.7 months (95% CI 3.9–NR). Conclusions Pazopanib was reasonably well tolerated with no unexpected toxicities. Pazopanib as a single agent has marginal activity in unselected heavily pretreated patients with advanced GIST. PMID:24356634

  9. Know thy neighbor: stromal cells can contribute oncogenic signals

    NASA Technical Reports Server (NTRS)

    Tlsty, T. D.; Hein, P. W.

    2001-01-01

    Although the stroma within carcinogenic lesions is known to be supportive and responsive to tumors, new data increasingly show that the stroma also has a more active, oncogenic role in tumorigenesis. Stromal cells and their products can transform adjacent tissues in the absence of pre-existing tumor cells by inciting phenotypic and genomic changes in the epithelial cells. The oncogenic action of distinctive stromal components has been demonstrated through a variety of approaches, which provide clues about the cellular pathways involved.

  10. Activity of c-Met/ALK Inhibitor Crizotinib and Multi-Kinase VEGF Inhibitor Pazopanib in Metastatic Gastrointestinal Neuroectodermal Tumor Harboring EWSR1-CREB1 Fusion.

    PubMed

    Subbiah, Vivek; Holmes, Oliver; Gowen, Kyle; Spritz, Daniel; Amini, Behrang; Wang, Wei-Lien; Schrock, Alexa B; Meric-Bernstam, Funda; Zinner, Ralph; Piha-Paul, Sarina; Zarzour, Maria; Elvin, Julia A; Erlich, Rachel L; Stockman, David L; Vergilio, Jo-Anne; Suh, James H; Stephens, Philip J; Miller, Vincent; Ross, Jeffrey S; Ali, Siraj M

    2016-01-01

    Malignant gastrointestinal neuroectodermal tumor (GNET) is an aggressive rare tumor, primarily occurring in young adults with frequent local-regional metastases and recurrence after local control. The tumor is characterized by the presence of EWSR1-ATF1 or EWSR1-CREB1 and immunohistochemical positivity for S-100 protein without melanocytic marker positivity. Due to poor responses to standard sarcoma regimens, GNET has a poor prognosis, and development of effective systemic therapy is desperately needed to treat these patients. Herein, we present a patient with a small bowel GNET who experienced recurrent hepatic and skeletal metastases after a primary resection. Comprehensive genomic profiling (CGP) in the course of clinical care with DNA and RNA sequencing demonstrated the presence of an exon 7 to exon 6 EWSR1-CREB1 fusion in the context of a diploid genome with no other genomic alterations. In a clinical trial, the patient received a combination of 250 mg crizotinib with 600 mg pazopanib quaque die and achieved partial response and durable clinical benefit for over 2.8 years, and with minimal toxicity from therapy. Using a CGP database of over 50,000 samples, we identified 11 additional cases that harbor EWSR1-CREB1 and report clinicopathologic characteristics, as these patients may also benefit from such a regimen.

  11. Somatostatin receptor imaging with (111)In-pentetreotide in gastro-intestinal tract and lung neuroendocrine tumors-Impact on targeted treatment.

    PubMed

    Gerasimou, George; Moralidis, Efstratios; Gotzamani-Psarrakou, Anna

    2010-01-01

    Somatostatin is a neuropeptide that confers a wide range of pharmacological properties. Indium-111-tagged pentetreotide ((111)In-P) is a radiolabeled analogue of somatostatin indicated for the in vivo scintigraphic localization of neuroendocrine tumors (NET). In cases of NET of the gastro-intestinal tract we describe the sensitivity compared to conventional anatomical imaging modalities and especially the possibility that (111)In-P may change therapeutic management into up one fourth of the patients. In cases of small cell lung carcinoma it has been used for the evaluation of somatostatin receptor status and a substantial tool for differentiation between limited and extensive disease, especially when combined with anatomical imaging methods. We also describe the radiolabeled with yttrium-90 or lutetium-177 somatostatin analogue peptides in the treatment of NET and also the use of (111)In-P for the selection of patients for targeted treatment.

  12. Cross-talk between chronic lymphocytic leukemia (CLL) tumor B cells and mesenchymal stromal cells (MSCs): implications for neoplastic cell survival

    PubMed Central

    Facco, Monica; Chiodin, Giorgia; Frezzato, Federica; Martini, Veronica; Gattazzo, Cristina; Lessi, Federica; Giorgi, Carlo Alberto; Visentin, Andrea; Castelli, Monica; Severin, Filippo; Zambello, Renato; Piazza, Francesco; Semenzato, Gianpietro; Trentin, Livio

    2015-01-01

    Leukemic cells from Chronic Lymphocytic Leukemia (CLL) patients interact with stromal cells of the surrounding microenvironment. Mesenchymal Stromal Cells (MSCs) represent the main population in CLL marrow stroma, which may play a key role for disease support and progression. In this study we evaluated whether MSCs influence in vitro CLL cell survival. MSCs were isolated from the bone marrow of 46 CLL patients and were characterized by flow cytometry analysis. Following co-culture of MSCs and leukemic B cells, we demonstrated that MSCs were able to improve leukemic B cell viability, this latter being differently dependent from the signals coming from MSCs. In addition, we found that the co-culture of MSCs with leukemic B cells induced an increased production of IL-8, CCL4, CCL11, and CXCL10 chemokines. As far as drug resistance is concerned, MSCs counteract the cytotoxic effect of Fludarabine/Cyclophosphamide administration in vivo, whereas they do not protect CLL cells from the apoptosis induced by the kinase inhibitors Bafetinib and Ibrutinib. The evidence that leukemic clones are conditioned by environmental stimuli suggest new putative targets for therapy in CLL patients. PMID:26517523

  13. Gastrointestinal tract spindle cell lesions--just like real estate, it's all about location.

    PubMed

    Voltaggio, Lysandra; Montgomery, Elizabeth A

    2015-01-01

    Interpretation of gastrointestinal tract mesenchymal lesions is simplified merely by knowing in which anatomic layer they are usually found. For example, Kaposi sarcoma is detected on mucosal biopsies, whereas inflammatory fibroid polyp is nearly always in the submucosa. Gastrointestinal stromal tumors (GISTs) are generally centered in the muscularis propria. Schwannomas are essentially always in the muscularis propria. Mesenteric lesions are usually found in the small bowel mesentery. Knowledge of the favored layer is even most important in interpreting colon biopsies, as many mesenschymal polyps are encountered in the colon. Although GISTs are among the most common mesenchymal lesions, we will concentrate our discussion on other mesenchymal lesions, some of which are in the differential diagnosis of GIST, and point out some diagnostic pitfalls, particularly in immunolabeling.

  14. A typical presentation of a rare cause of obscure gastrointestinal bleeding

    PubMed Central

    Reuter, Stefan; Bettenworth, Dominik; Mees, Sören Torge; Neumann, Jörg; Beyna, Torsten; Domschke, Wolfram; Wessling, Johannes; Ullerich, Hansjörg

    2011-01-01

    A 52-year-old white woman had suffered from intermittent gastrointestinal (GI) bleeding for one year. Upper GI endoscopy, colonoscopy and peroral double-balloon enteroscopy (DBE) did not detect any bleeding source, suggesting obscure GI bleeding. However, in videocapsule endoscopy a jejunal ulceration without bleeding signs was suspected and this was endoscopically confirmed by another peroral DBE. After transfusion of packed red blood cells, the patient was discharged from our hospital in good general condition. Two weeks later she was readmitted because of another episode of acute bleeding. Multi-detector row computed tomography with 3D reconstruction was performed revealing a jejunal tumor causing lower gastrointestinal bleeding. The patient underwent exploratory laparotomy with partial jejunal resection and end-to-end jejunostomy for reconstruction. Histological examination of the specimen confirmed the diagnosis of a low risk gastrointestinal stromal tumor (GIST). Nine days after surgery the patient was discharged in good health. No signs of gastrointestinal rebleeding occurred in a follow-up of eight months. We herein describe the complex presentation and course of this patient with GIST and also review the current approach to treatment. PMID:21403816

  15. Tumor cell and connective tissue cell interactions in human colorectal adenocarcinoma. Transfer of platelet-derived growth factor-AB/BB to stromal cells.

    PubMed Central

    Sundberg, C.; Branting, M.; Gerdin, B.; Rubin, K.

    1997-01-01

    Mechanisms underlying stimulation of platelet-derived growth factor (PDGF) beta-receptors expressed on connective tissue cells in human colorectal adenocarcinoma were investigated in this study. PDGF-AB/BB, but not PDGF receptors, was expressed by tumor cells in situ, as well as in tumor cell isolates of low passage from human colorectal adenocarcinoma. In an experimental co-culture system, conditioned medium from tumor cells only marginally activated PDGF beta-receptors expressed on fibroblasts. In contrast, co-culturing of the two cell types led to a marked PDGF beta-receptor activation. Functional PDGF-AB/BB was found to be associated with heparinase-I-sensitive components on the tumor cell surface. PDGF-AB/BB, isolated from heparinase-I-sensitive cell surface components, induced a marked activation of PDGF beta-receptors. Furthermore, co-culturing tumor cells together with fibroblasts led to a sustained activation of PDGF beta-receptors expressed on fibroblasts. Double immunofluorescence staining of tissue sections from human colorectal adenocarcinoma, combined with computer-aided image analysis, revealed that nonproliferating tumor cells were the predominant cellular source of PDGF-AB/BB in the tumor stroma. In addition, PDGF-AB/BB-expressing tumor cells were found juxtapositioned to microvascular cells expressing activated PDGF beta-receptors. Confocal microscopy revealed a cytoplasmic and cell-membrane-associated expression of PDGF-AB/BB in tumor cells situated in the stroma. In contrast, epithelial cells situated in normal or tumorous acinar structures revealed only a cell-membrane-associated PDGF-AB/BB expression. The is vitro and in situ results demonstrate that tumor cells not only facilitate but also have the ability to modulate connective tissue cell responsiveness to PDGF-AB/BB in a paracrine fashion, through direct cell-cell interactions in human colorectal adenocarcinoma. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 PMID:9250160

  16. Delta-ALA-mediated fluorescence spectroscopy of gastrointestinal tumors: comparison of in vivo and in vitro results

    NASA Astrophysics Data System (ADS)

    Vladimirov, B.; Borisova, E.; Avramov, L.

    2007-06-01

    The limitations of standard endoscopy for detection of dysplastic changes of mucosa are significant challenge and initiate development of new photodiagnostic techniques, additional to diagnostic possibilities of standard endoscopic equipment. One of the most widely examined optical modalities is the laser- or light-induced fluorescence spectroscopy (LIFS), because of its rapid and highly sensitive response to early biochemical and morphological changes in biological tissues. In the recent study delta-aminolevulinic acid/protoporphyrin IX is used as fluorescent marker for dysplasia and tumor detection in esophagus and stomach. The δ -ALA is administered per os six hours before measurements at dose 20mg/kg weight. High-power light-emitting diode at 405 nm is used as an excitation source. Special opto-mechanical device is built to use the light guide of standard video-endoscopic system. Through endoscopic instrumental channel a fiber is applied to return information about fluorescence to microspectrometer. The fluorescence detected from in vivo tumor sites has very complex spectral origins. It consists of autofluorescence, fluorescence from exogenous fluorophores and re-absorption from the chromophores accumulated in the tissue investigated. Mucosa autofluorescence lies at 450-600 nm region. The fluorescence of PpIX is clearly pronounced at the 630-710 nm region. Deep minima in the tumor fluorescence signals are observed in the region 540-575 nm, related to hemoglobin re-absorption. Such high hemoglobin content is an indication of the tumors vascularization and it is clearly pronounced in all dysplastic and tumor sites investigated. After formalin conservation for in vitro samples hemoglobin absorption is strongly reduced that increases mucous fluorescence signal in green-yellow spectral region. Simultaneously the maxima at 635 nm and 720 nm are reduced.

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

    PubMed

    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.

  18. Stromal-Based Signatures for the Classification of Gastric Cancer.

    PubMed

    Uhlik, Mark T; Liu, Jiangang; Falcon, Beverly L; Iyer, Seema; Stewart, Julie; Celikkaya, Hilal; O'Mahony, Marguerita; Sevinsky, Christopher; Lowes, Christina; Douglass, Larry; Jeffries, Cynthia; Bodenmiller, Diane; Chintharlapalli, Sudhakar; Fischl, Anthony; Gerald, Damien; Xue, Qi; Lee, Jee-Yun; Santamaria-Pang, Alberto; Al-Kofahi, Yousef; Sui, Yunxia; Desai, Keyur; Doman, Thompson; Aggarwal, Amit; Carter, Julia H; Pytowski, Bronislaw; Jaminet, Shou-Ching; Ginty, Fiona; Nasir, Aejaz; Nagy, Janice A; Dvorak, Harold F; Benjamin, Laura E

    2016-05-01

    Treatment of metastatic gastric cancer typically involves chemotherapy and monoclonal antibodies targeting HER2 (ERBB2) and VEGFR2 (KDR). However, reliable methods to identify patients who would benefit most from a combination of treatment modalities targeting the tumor stroma, including new immunotherapy approaches, are still lacking. Therefore, we integrated a mouse model of stromal activation and gastric cancer genomic information to identify gene expression signatures that may inform treatment strategies. We generated a mouse model in which VEGF-A is expressed via adenovirus, enabling a stromal response marked by immune infiltration and angiogenesis at the injection site, and identified distinct stromal gene expression signatures. With these data, we designed multiplexed IHC assays that were applied to human primary gastric tumors and classified each tumor to a dominant stromal phenotype representative of the vascular and immune diversity found in gastric cancer. We also refined the stromal gene signatures and explored their relation to the dominant patient phenotypes identified by recent large-scale studies of gastric cancer genomics (The Cancer Genome Atlas and Asian Cancer Research Group), revealing four distinct stromal phenotypes. Collectively, these findings suggest that a genomics-based systems approach focused on the tumor stroma can be used to discover putative predictive biomarkers of treatment response, especially to antiangiogenesis agents and immunotherapy, thus offering an opportunity to improve patient stratification. Cancer Res; 76(9); 2573-86. ©2016 AACR.

  19. Endoscopic submucosal tunnel dissection of upper gastrointestinal submucosal tumors: A comparative study of hook knife vs hybrid knife

    PubMed Central

    Zhou, Jie-Qiong; Tang, Xiao-Wei; Ren, Yu-Tang; Wei, Zheng-Jie; Huang, Si-Lin; Gao, Qiao-Ping; Zhang, Xiao-Feng; Yang, Jian-Feng; Gong, Wei; Jiang, Bo

    2017-01-01

    AIM To compare the efficacy and safety of a hook knife (HO) with a hybrid knife (HK) during endoscopic submucosal tunnel dissection (ESTD) procedure. METHODS Between August 2012 and December 2015, the ESTD procedure was performed for 83 upper GI submucosal lesions, which originated from the muscularis propria layer identified by upper endoscopy and endoscopic ultrasonography. Of these, 34 lesions were treated by a HO, whereas 49 lesions were treated by a HK. Data regarding age, gender, presenting symptoms, tumor location and size, procedure time, complications, en bloc resection rate and others were analyzed and compared between the two groups. RESULTS There were no significant differences in the age, gender, presenting symptoms and tumor location between the two groups. ESTD was successfully completed in all the patients, and no case was converted to laparoscopy. The mean procedure time was significantly shorter in the HK group than in the HO group (41.3 ± 20.3 min vs 57.2 ± 28.0 min, P = 0.004). The mean frequency of device exchange was 1.4 ± 0.6 in the HK group and significantly less than 3.3 ± 0.6 in the HO group (P < 0.001). The differences in tumor size and histopathological diagnoses were not significant between the two groups (P = 0.813, P = 0.363, respectively). Both groups had an equal en bloc resection rate and complete resection rate. Additionally, the complication rate was similar between the two groups (P = 0.901). During the follow-up, no recurrence occurred in either group. CONCLUSION We demonstrate for the first time that HO and HK do not differ in efficacy or safety, but HK reduces the frequency of device exchange and procedure time. PMID:28348490

  20. Stromal cells can contribute oncogenic signals

    NASA Technical Reports Server (NTRS)

    Tlsty, T. D.

    2001-01-01

    The majority of studies of neoplastic transformation have focused attention on events that occur within transformed cells. These cell autonomous events result in the disruption of molecular pathways that regulate basic activities of the cells such as proliferation, death, movement and genomic integrity. Other studies have addressed the microenvironment of tumor cells and documented its importance in supporting tumor progression. Recent work has begun to expand on these initial studies of tumor microenvironment and now provide novel insights into the possible initiation and progression of malignant cells. This review will address the transforming effect of stromal cells on epithelial components. Copyright 2001 Academic Press.

  1. Role of contrast-enhanced harmonic endoscopic ultrasound in submucosal tumors

    PubMed Central

    Alvarez-Sanchez, Maria Victoria; Gincul, Rodica; Lefort, Christine; Napoleon, Bertrand

    2016-01-01

    With the widespread use of endoscopy, gastrointestinal submucosal lesions are now more commonly discovered. Although endoscopic ultrasound (EUS) is superior to all other imaging techniques for the diagnosis of submucosal tumors (SMTs), it is still suboptimal for differentiating hypoechoic lesions arising from the fourth sonographic gastrointestinal wall layer, which encompass tumors with very different prognosis. EUS tissue acquisition has provided with the unique opportunity to obtain histological confirmation, but it is not accurate enough to evaluate the malignant potential of gastrointestinal stromal tumors (GISTs). In the last years, contrast-enhanced harmonic EUS (CH-EUS) emerged as a powerful imaging modality to assess the microperfusion patterns of pancreatic tumors. Based on the distinct microvascularity of malignant SMTs, it was hypothesized that CH-EUS might also assist in the differential diagnosis of SMTs. Preliminary experience in this field is now available and suggests CH-EUS as a performant modality to distinguish between benign SMTs and GISTs and to evaluate the malignant potential of GISTs. High expectations are also relied on CH-EUS for the monitoring of antiangiogenic treatments of GISTs and the evaluation of gastrointestinal neuroendocrine tumors (NETs). PMID:28000626

  2. Role of contrast-enhanced harmonic endoscopic ultrasound in submucosal tumors.

    PubMed

    Alvarez-Sanchez, Maria Victoria; Gincul, Rodica; Lefort, Christine; Napoleon, Bertrand

    2016-01-01

    With the widespread use of endoscopy, gastrointestinal submucosal lesions are now more commonly discovered. Although endoscopic ultrasound (EUS) is superior to all other imaging techniques for the diagnosis of submucosal tumors (SMTs), it is still suboptimal for differentiating hypoechoic lesions arising from the fourth sonographic gastrointestinal wall layer, which encompass tumors with very different prognosis. EUS tissue acquisition has provided with the unique opportunity to obtain histological confirmation, but it is not accurate enough to evaluate the malignant potential of gastrointestinal stromal tumors (GISTs). In the last years, contrast-enhanced harmonic EUS (CH-EUS) emerged as a powerful imaging modality to assess the microperfusion patterns of pancreatic tumors. Based on the distinct microvascularity of malignant SMTs, it was hypothesized that CH-EUS might also assist in the differential diagnosis of SMTs. Preliminary experience in this field is now available and suggests CH-EUS as a performant modality to distinguish between benign SMTs and GISTs and to evaluate the malignant potential of GISTs. High expectations are also relied on CH-EUS for the monitoring of antiangiogenic treatments of GISTs and the evaluation of gastrointestinal neuroendocrine tumors (NETs).

  3. Bone Marrow-Derived Cells May Not Be the Original Cells for Carcinogen-Induced Mouse Gastrointestinal Carcinomas

    PubMed Central

    Yang, Chen; Gu, Liankun; Deng, Dajun

    2013-01-01

    Aim It has been reported that bone marrow-derived cells (BMDC) can be original cells of mouse gastric cancers induced by Helicobacter felis (H. felis) infection. However, it is unknown whether BMDCs are also the original cells of mouse gastrointestinal cancers induced by gastric carcinogens N-nitroso-N-methylurea (NMU) and H. felis infection. Methods C57BL/6 recipient mice were initially irradiated with 10Gy X-ray, reconstituted with bone marrow cells from the C57BL/6-Tg (CAG-EGFP) donor mice to label BMDCs with green fluorescence protein (GFP). After 4 weeks of recovery, the bone marrow-transplanted mice were given NMU in drinking water (240 ppm) and subsequently infected with H. felis by gavage. Eighty weeks later, all mice were euthanized for pathological examination. The BMDCs expressing GFP were detected in tissues using direct GFP fluorescence confocal microscopy analysis and immunohistochemistry staining (IHC) assays. Results Neoplastic lesions were induced by NMU treatment and/or H. felis infection at the antrum of the glandular stomach and small intestine. In the direct GFP fluorescence confocal assay, GFP(+) epithelial cell cluster or glands were not observed in these gastrointestinal tumors, however, most GFP(+) BMDCs sporadically located in the tumor stromal tissues. Some of these GFP(+) stromal BMDCs co-expressed the hematopoietic marker CD45 or myofibroblasts markers αSMA and SRF. In the indirect GFP IHC assay, similar results were observed among 11 gastric intraepithelial neoplasia lesions and 2 small intestine tumors. Conclusion These results demonstrated that BMDCs might not be the source of gastrointestinal tumor cells induced by NMU and/or H. felis infection. PMID:24260263

  4. Sertoli-Leydig cell tumor

    MedlinePlus

    Sertoli-stromal cell tumor; Arrhenoblastoma; Androblastoma; Ovarian cancer - Sertoli-Leydig cell tumor ... The Sertoli cells are normally located in the male reproductive glands (the testes). They feed sperm cells. The Leydig cells, also ...