Recent advances and novel agents for gastrointestinal stromal tumor (GIST)

Contemporary advancements have had little impact on the treatment of gastric cancer (GC), the world??s second highest cause of cancer death. Agents targeting human epidermal growth factor receptor mediated pathways have been a common topic of contemporary cancer research, including monoclonal antibodies (mAbs) and receptor tyrosine kinase inhibitors (TKIs). Trastuzumab is the first target agent evidencing improvements in overall survival in HER2-positive (human epidermal growth factor receptor 2) gastric cancer patients. Agents targeting vascular epithelial growth factor (VEGF), mammalian target of rapamycin (mTOR), and other biological pathways are also undergoing clinical trials, with some marginally positive results. Effective targeted therapy requires patient selection based on predictive molecular biomarkers. Most phase III clinical trials are carried out without patient selection; therefore, it is hard to achieve personalized treatment and to monitor patient outcome individually. The trend for future clinical trials requires patient selection methods based on current understanding of GC biology with the application of biomarkers.     

A gastrointestinal stromal tumor (GIST) masquerading as an ovarian mass

Background

Malignant gastrointestinal stromal tumors (GIST) are rare mesenchymal tumors originating in the wall of the gastrointestinal tract. Myogenic gastrointestinal stromal tumor, a distinctive morphologic variant is characterized by an unusually prominent myxoid stromal background.

Case presentation

We report a case of myxoid variant of GIST in a 42 years old woman presenting as an epigastric mass associated to an ovarian cyst and elevated CA-125. Histologically, the lesions was composed of a proliferation of spindle cells in an abundant myxoid stroma, without evidence of atypia or anaplasia. Immunohistochemical stains showed strong positive staining with muscle actin, positive staining with CD34 and weak positive staining with CD117, while showed negative for S-100.

Conclusion

At surgery every effort should be made to identify the origin of the tumor. A complete surgical removal of the tumor should be obtained, as this is the only established treatment that offers long term survival.     

A rare giant gastrointestinal stromal tumor (GIST) of the stomach traversing the upper abdomen: a case report and literature review

ABSTRACT: This article presents a 66-year-old woman with a huge GIST of stomach that traverses the upper abdomen. With only the predominant abdominal sign featuring a palpable huge mass, but none special physical findings and routine blood as well as biochemical markers, it could hardly judge where the mass drive from upon the images. Furthermore, many important blood vessels had a complex relationship with the mass according to radiological findings. An exploratory laparotomy revealed a huge tumor that protrude from prior wall of stomach fundus, lesser curvature of stomach side, measuring approximately 21 x 34 x 11 cm in diameter and weighing 5.5Kg. A completely resection was decided on the tumor and the department of pathology immunohistochemically characterized it (CD117, CD34, Dog-1, etc) as a GIST of stomach. Preoperatively diagnosis of GISTs is still sometimes puzzling. Hoping the presentation of this rare case and the literature review could benefit others in similar problems.     

Role of c-kit/SCF in cause and treatment of gastrointestinal stromal tumors (GIST)

c-Kit encodes for the receptor tyrosine kinase (RTK) and belongs to type III receptor family. This includes platelet derived growth factor (PDGF) alpha and beta and macrophage colony stimulating factor (mCSF) apart from others. Their characteristic features are the presence of five immunologlobulin like domains in the extracellular region and 70-100 residues long kinase insert domain in the cytoplasmic region. The RTKs activate several signaling pathways within the cells leading to cell proliferation, differentiation, migration or metabolic changes. The Kit ligand-stem cell factor (SCF) induces a rapid and complete receptor dimerization resulting in activation by autophosphorylation of the catalytic tyrosine kinase and generation of signal transduction leading to regulation of cell growth. Various mutations in c-kit such as insertions and deletions (without affecting reading frame) and point mutations in the inhibitory juxtamembrane (JM) domain encoded by exon 11 have been reported in gastrointestinal stromal tumors (GISTs). Thus, c-kit signaling is believed to play a role in tumorigenesis. Efforts are being made to control and treat these tumors by blocking kit signaling using Imatinib with varying degrees of success. This review deals with the features of c-kit, its ligand and roles in gastrointestinal stromal tumors.     

Primary gastrointestinal stromal tumor of the mesentery

Primary solid tumors of the mesentery are very rare. The authors found a bulky gastrointestinal stromal tumor (GIST) in the mesentery. The stomach and the intestines were tumor-free.     

Regorafenib regresses an imatinib-resistant recurrent gastrointestinal stromal tumor (GIST) with a mutation in exons 11 and 17 of c-kit in a patient-derived orthotopic xenograft (PDOX) nude mouse model

Gastrointestinal stromal tumor (GIST) with a mutation in exons 11 and 17 of c-kit is a rare type of sarcoma. The aim of this study was to determine drug sensitivity for a regionally-recurrent case of GIST using a patient-derived orthotopic xenograft (PDOX) model. The PDOX model was established in the anterior wall of the stomach. GIST PDOX models were randomized into 5 groups of 6 mice each when the tumor volume reached 60 mm³: G1, control group; G2, imatinib group (oral administration (p.o.), daily, for 3 weeks); G3, sunitinib group (p.o., daily, for 3 weeks); G4, regorafenib (p.o., daily, for 3 weeks); G5, pazopanib (p.o., daily, for 3 weeks). All mice were sacrificed on day 22. Tumor volume was evaluated on day 0 and day 22 by laparotomy. Body weight were measured 2 times per week. Though regorafenib is third-line therapy for GIST, it was the most effective drug and regressed the tumor significantly (p < 0.001). Sunitinib suppressed tumor growth compared to the control group (p = 0.002). Imatinib, first-line therapy for GIST, and pazopanib did not have significant efficacy compared to the control group (p = 0.886, p = 0.766). The implications of this result is discussed for GIST patients.     

Gastrointestinal stromal tumors (GIST): Facing cell death between autophagy and apoptosis

Autophagy and apoptosis are 2 fundamental biological mechanisms that may cooperate or be antagonistic, although both are involved in deciding the fate of cells in physiological or pathological conditions. These 2 mechanisms coexist simultaneously in cells and share common upstream signals and stimuli. Autophagy and apoptosis play pivotal roles in cancer development. Autophagy plays a key function in maintaining tumor cell survival by providing energy during unfavorable metabolic conditions through its recycling mechanism, and supporting the high energy requirement for metabolism and growth. This review focuses on gastrointestinal stromal tumors and cell death through autophagy and apoptosis, taking into account the involvement of both of these processes in tumor development and growth and as mechanisms of drug resistance. We also focus on the crosstalk between autophagy and apoptosis as an emerging field with major implications for the development of novel therapeutic options.     

A case of gastrointestinal stromal tumor with spontaneous rupture in the greater omentum

Background

Although GIST generally occurs in the digestive tract, such as the stomach, and small and small intestine primarily, Omental GIST tumours are very rare.

Case Presentation

A 63-year-old male patient, who recognized an abdominal tumor 1 year before admission, had a slight expansion of the tumor, reduction of the body and malaise, was consulted to our hospital. Abdominal CT and MRI revealed a cystic lesion of 26 cm in diameter with a clear boundary from immediately below the interseptum to the pelvic cavity, and imaged the septum and cystic wall. We considered that the patient had a cystic tumor in the abdomen, of which the primary lesion was unknown, and scheduled surgery. The patient unfortunately deteriorated with shock and sudden pain in the abdomen. Wediagnosed tumor rapture, and emergency surgery was performed. The tumor, weighing 3,600 g, was mostly cystic, and filled with sanguinous fluid and clot. Histologically, the tumor was composed of spindle cells, and was positive for c-KIT (CD117), slightly positive for alpha-smooth muscle actin (SMA), and S-100 protein positive. Based on these findings, the tumor was diagnosed as GIST primarily occurring in the greater omentum.

Conclusion

We experienced a rare case of GIST which originated from the greater omentum. Recently, the prognosis of GIST has been improved since the treatment with Imatinib.It is necessary to consider the diagnosis of GIST on encountering a mass in the greater omentum.

     

Undifferentiated embryonal sarcoma of the liver mimicking acute appendicitis. Case report and review of the literature

Background

Parathyroid carcinoma is a rare cause of primary hyperparathyroidism and may be associated with significant disease related morbidity and mortality. Preoperative diagnosis remains a challenge, which may jeopardize appropriate and successful patient treatment.

Case presentation

We report a case of parathyroid carcinoma diagnosed in a 60-year-old woman that presented with a tender nodule located at the left lower thyroid pole and had been present for several years. Ultrasound examination revealed a 2.7 × 1.6 × 2.7 cm mass within the lower left lobe of the thyroid with cystic and solid areas. Lab measurement of the intact PTH level revealed it to be three times the upper limit of normal and the serum calcium level was within normal limits. A left thyroid lobectomy and isthmusectomy was carried out. Histopathological evaluation was diagnostic for a parathyroid carcinoma. At greater than two years of follow-up, the patient has had no evidence of disease recurrence and her serum PTH and calcium levels have remained within normal.

Conclusion

Parathyroid carcinoma is a rare endocrine tumor which must be considered in the differential diagnosis of a nodular thyroid mass. En bloc resection remains the treatment of choice for this malignancy. Disease prognosis is influenced by the extent of the initial resection, the presence of metastases, and adequate long-term follow-up.     

Dual tumours in the GI tract: synchronous and metachronous stromal (GIST) and epithelial/neuroendocrine neoplasms

Gastrointestinal stromal tumours (GIST) constitute the most frequent group of mesenchymal tumours in the gastrointestinal tract (GI). During the last several decades major advances have been taken in the diagnostics, treatment, and understanding of its pathogenesis. However, much less is known about the either metachronous or synchronous concurrence of GIST and other tumours of different histogenesis. In the present study clinicopathological data of 43 patients with histologically proved gastrointestinal stromal tumour were studied mainly in regard of the occurrence of a secondary neoplasm. Among the 43, 7 cases were found with secondary tumour mainly of epithelial origin. In three cases (cases 3, 5, and 7) GIST concurred with colorectal adenocarcinoma, in one case (case 1) GIST occurred in a patient with a 3-years-history of chronic lymphocytic leukaemia (CLL), in other two (cases 2 and 4) the stromal tumour was combined with in situ adenocarcinoma of the stomach and carcinoid of the pancreas, respectively. In case 6, GIST concurred with a duodenal Brunner gland adenoma. In five cases the stromal tumour and the other neoplasm occurred synchronously, and in four of them, being the stromal tumour clinically silent, GISTs were intraoperative findings. This confirms the importance of surgical intraabdominal control before closure. In one hand the repeated concurrence of GIST and colorectal adenocarcinoma in our series, and on the other hand, that of GIST and adenocarcinoma of the stomach in the literature, may indicate an at least partly common factor, which may be involved in the pathogenesis of these neoplasms.     

CD133在胃肠间质瘤的表达及其临床意义

目的 探讨胃肠间质瘤（gastrointestinal stromal tumor,GIST）中的CD133的表达及其与GIST临床病理特征的关系.方法 采用免疫组织化学法,检测122例胃肠间质瘤患者组织中的CD133、CD117、CD34、DOG-1、KI-67的表达情况.结果 CD133、CD117、CD34 、DOG-1、KI-67的阳性表达率分别为74.6%（91/122）、98.4%（120/122）、86.9%（106/122）、95.1%（116/122）、47.5%（58/122）.CD133的表达水平与胃肠间质瘤危险度分组高低、核分裂像数目、肿瘤部位有关（P〈0.05）,而与患者性别、年龄、肿瘤大小无明显相关性（P〉0.05）.CD133的表达水平与DOG-1的表达水平无明显相关性（P〉0.05）,而与CD117、CD34、KI-67的表达水平呈正相关.结论 CD133蛋白的表达可能与GIST的恶性行为与预后有关,与CD117、CD34和DOG-1联合检测对于判断GIST的病理性质可能具有重要价值.     

Imatinib potentiates antitumor T cell responses in gastrointestinal stromal tumor through the inhibition of Ido

Imatinib mesylate targets mutated KIT oncoproteins in gastrointestinal stromal tumor (GIST) and produces a clinical response in 80% of patients. The mechanism is believed to depend predominantly on the inhibition of KIT-driven signals for tumor-cell survival and proliferation. Using a mouse model of spontaneous GIST, we found that the immune system contributes substantially to the antitumor effects of imatinib. Imatinib therapy activated CD8(+) T cells and induced regulatory T cell (T(reg) cell) apoptosis within the tumor by reducing tumor-cell expression of the immunosuppressive enzyme indoleamine 2,3-dioxygenase (Ido). Concurrent immunotherapy augmented the efficacy of imatinib in mouse GIST. In freshly obtained human GIST specimens, the T cell profile correlated with imatinib sensitivity and IDO expression. Thus, T cells are crucial to the antitumor effects of imatinib in GIST, and concomitant immunotherapy may further improve outcomes in human cancers treated with targeted agents.     

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

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.     

c-kit immunocytochemical staining in the cytologic diagnosis of metastatic gastrointestinal stromal tumor. A report of two cases

BACKGROUND: Gastrointestinal stromal tumor (GIST) is a distinct group of mesenchymal neoplasms recently shown to exhibit differentiation toward interstitial cells of Cajal (ICC). C-kit (CD117), an immunocytochemical marker consistently expressed in normal ICC, is demonstrable in 81-100% of GISTs. We report two cases wherein immunocytochemical staining for c-kit aided in the diagnosis of metastatic GIST in the liver. CASES: Two patients, a 37-year-old female (case 1) and a 76-year-old male (case 2), presented with multiple nodules in the liver. They had a history of small bowel GIST resected 11 and 1 year earlier, respectively. Fine needle aspiration of the liver nodules showed loose aggregates or fascicles of spindle cells with elongated to oval nuclei, rare paranuclear vacuoles and eosinophilic cytoplasm. The spindle cells showed minimal (case 1) to moderate nuclear pleomorphism (case 2), with occasional mitotic figures seen in case 2. Immunocytochemical staining revealed strong and diffuse staining for c-kit; it was negative for actin, desmin, CD34 and S-100 protein. Thus, a diagnosis of metastatic GIST was rendered. Histologic review of the primary small bowel GISTs of both cases and the subsequently resected liver nodules in case 1 confirmed the diagnosis. CONCLUSION: Metastatic GIST may pose diagnostic problems due to its broad morphologic spectrum and variable cytologic atypia; in particular, distinction from leiomyosarcoma and other mesenchymal tumors is difficult. The diagnostic difficulty is compounded when the prior history of gastrointestinal tumor is not available or forgotten and when GIST is the initial presentation of the tumor. C-kit is a highly sensitive and reliable immunocytochemical marker that can aid in the diagnosis.     

Functional role of the Ca-activated Cl channel DOG1/TMEM16A in gastrointestinal stromal tumor cells

DOG1, a Ca²⁺-activated Cl⁻ channel (CaCC), was identified in 2004 to be robustly expressed in gastrointestinal stromal tumors (GIST). It was rapidly included as a tumor marker in routine diagnostics, but the functional role remained unknown. CaCCs are important regulators of normal physiological functions, but also implicated in tumorigenesis, cancer progression, metastasis, cell migration, apoptosis, proliferation and viability in several malignancies. We therefore investigated whether DOG1 plays a role in the three latter in GIST by utilizing in vitro cell model systems. Confocal microscopy identified different subcellular localizations of DOG1 in imatinib-sensitive and imatinib-resistant cells. Electrophysiological studies confirmed that DOG1-specific pharmacological agents possess potent activating and inhibiting properties. Proliferation assays showed small effects up to 72 h, and flow cytometric analysis of adherent cells with 7-AAD/Annexin V detected no pharmacological effects on viable GIST cells. However, inhibition of DOG1 conveyed pro-apoptotic effects among early apoptotic imatinib-resistant cells. In conclusion, DOG1 generates Cl⁻ currents in GIST that can be regulated pharmacologically, with small effects on cell viability and proliferation in vitro. Inhibition of DOG1 might act pro-apoptotic on some early apoptotic GIST cell populations. Further studies are warranted to fully illuminate the function of DOG1 and its potential as therapeutic target.