Endoscopically Assisted Transumbilical Single-Incision Laparoscopic Gastric Resection for GIST Treatment

Purpose: Complete surgical resection with negative margins without lymphadenectomy is the treatment of choice for nonmetastatic Gastrointestinal Stromal Tumors (GISTs). Laparoscopic resection of gastric GISTs <5 cm is an acceptable and oncologically feasible, safe, and effective treatment. We present our experience of an endoscopically assisted minimally invasive transumbilical single-incision laparoscopic (SILS) technique for gastric GISTs resection. Methods: Four patients with small gastric GISTs ≤5 cm located on the greater curvature or the anterior wall were resected with SILS by using a lesion-lifting technique under the guidance of flexible gastroscopy. Results: The technique was feasible and safe and offered significant advantages in locating the tumor and controlling the resection margins. There were no major intraoperative or postoperative complications, conversions, or tumor ruptures. Pathology showed low-risk GISTs resected with disease-free margins without tumor rupture. No recurrences have been observed. Conclusion: The endoscopically assisted SILS wedge gastrectomy is a feasible, safe, and advantageous technique for the treatment of the greater curvature or anterior wall gastric GISTs.     

Gastrointestinal stromal tumors of the rectum: Clinical,pathologic, immunohistochemical characteristics and prognostic analysis

Objective. To describe the clinical, pathological and immunohistochemical characteristics of rectal gastrointestinal stromal tumors (GISTs) and to correlate them with clinical outcomes. Material and methods. A retrospective review of 29 patients with surgically treated rectal GISTs during the period from 1997 to 2005 was undertaken. The NIH (National Institute of Health Consensus) criteria were applied. Results. All the rectal GISTs in our series originated in the lower half of the rectum and patients underwent primary surgery for complete resections; High-risk, intermediate-risk, low-risk and very low-risk GISTs were found in 11, 6, 5 and 7 patients, respectively. Necrosis, adjacent (mucosal or serosa) invasion and marked pleomorphisms were found in 10, 7 and 20 patients, respectively. Positive expression of CD117, CD34, SMA and S-100 was found in 28, 28, 7 and 3 patients, respectively. Twelve patients had recurrence or metastasis within the median disease-free survival time of 41 months. Among the patients who underwent local resections, the recurrence rate for low-risk and very low-risk GISTs was only 1/10; for intermediate-risk and high-risk GISTs, the recurrence rate after local resections was 3/4, which was higher than the recurrence and metastasis rate of 8/13 after laparotomy. Of the 12 patients with adverse outcomes, 4 patients underwent secondary complete resections; however, all 4 patients had further recurrences. On univariate analysis, risk classification (p=0.0002), necrosis (p=0.0205), adjacent invasion (p=0.0090) and marked pleomorphism (p=0.0480) were significant predictors of disease-free survival. In the Cox regression model, only the risk classification (p=0.012) was found to be an independent factor. Conclusions. We found that rectal GISTs arise predominantly in the lower half of the rectum and have high CD117 and CD34 expression. Local resection may be a good choice for very-low-risk and low-risk GISTs, but aggressive surgery may be more beneficial for high-risk and intermediate-risk GISTs. For patients with disease recurrence, the results of secondary surgery were poor. Only the NIH risk classification proved to be an independent prognostic factor for rectal GISTs, whereas the proof for other factors was insufficient.     

胃肠间质肿瘤临床病理与免疫组化特征

目的：探讨胃肠间质瘤（GISTs)临床病理、免疫组化及组织分型。方法：44例胃肠非上皮梭形细胞肿瘤常规检查，Vimentin、Desmin、SMA、S－100、CD34 5种抗体采用Envision法免疫组化检测。44例非上皮梭形细胞肿瘤中，GISTs 37例，占84．1％，良性GISTs 8例，潜在恶性GISTs 7例，恶性GISTs 22例。临床以消化道出血，疼痛多见。光镜下为梭形细胞和上皮样细胞两种基本成分。结果：37例GISTs中，Vimentin、Desmin、SMA、S－100、CD34阳性分别为94．6％、5．4％、43．2％、48．7％、89．2％，其中GISTs I型8例（21．6％），GISTs Ⅱ型10例（27．1％），GISTs Ⅲ型8例（21．6％），GISTs Ⅳ型11例（29．7％）。结论：GISTs是胃肠道最常见的间质性肿瘤，具有多向分化特性，HE形态类似，免疫组化在GISTs诊断中起主要作用，CD34有较高的特异性和敏感性。     

15例胃肠道间质瘤的临床病理分析

目的：探讨胃肠道问质瘤(GISTs)的组织学起源与病理特点。方法：对15例GISTs标本进行形态学观察和免疫组织化学染色及对比分析。结果：本组病例多以腹部包块、疼痛及消化道出血为首发症状，以梭形细胞型为主(93.3％)，CD117阳性率为100％，CD34阳性率为73．3％。结论：GISTs符合卡哈尔问质细胞来源。CD117及CD34对GISTs的诊断和治疗具有重要意义。     

Carney triad: case report and molecular analysis of gastric tumor

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the GI tract. Most of them are thought to be sporadic, but some arise in the settings of neurofibromatosis type I (NF-1) and the Carney triad. The Carney triad is a syndrome of unknown etiology, occurring predominantly in young females, comprising gastrointestinal stromal tumors, pulmonary chondromas, and extra-adrenal paragangliomas. GISTs of the Carney triad involve predominantly the body and the antrum of the stomach, are generally multifocal, and have a better prognosis than sporadic GISTs. We describe the clinical and pathological features of a case of Carney triad that featured multiple gastric GISTs, mediastinal paraganglioma, and esophageal leiomyoma. Ten years after gastric resection, the patient developed liver and peritoneal metastasis and was treated with Imatinib mesylate for 6 months with no change in the lesions. The molecular analysis of the GIST, the first reported in a gastric tumor from the triad, showed a wild-type KIT and PDGFRA genes.     

Combination of pimitespib (TAS-116) with sunitinib is an effective therapy for imatinib-resistant gastrointestinal stromal tumors

Despite the effectiveness of imatinib, most gastrointestinal stromal tumors (GISTs) develop resistance to the treatment, mainly due to the reactivation of KIT tyrosine kinase activity. Sunitinib, which inhibits the phosphorylation of KIT and vascular endothelial growth factor (VEGF) receptor, has been established as second-line therapy for GISTs. The recently-developed heat shock protein 90 (HSP90) inhibitor pimitespib (PIM; TAS-116) demonstrated clinical benefits in some clinical trials; however, the effects were limited. The aim of our study was therefore to clarify the effectiveness and mechanism of the combination of PIM with sunitinib for imatinib-resistant GISTs. We evaluated the efficacy and mechanism of the combination of PIM with sunitinib against imatinib-resistant GIST using imatinib-resistant GIST cell lines and murine xenograft models. In vitro analysis demonstrated that PIM and sunitinib combination therapy strongly inhibited growth and induced apoptosis in imatinib-resistant GIST cell lines by inhibiting KIT signaling and decreasing auto-phosphorylated KIT in the Golgi apparatus. In addition, PIM and sunitinib combination therapy enhanced antitumor responses in the murine xenograft models compared to individual therapies. Further analysis of the xenograft models showed that the combination therapy not only downregulated the KIT signaling pathway but also decreased the tumor microvessel density. Furthermore, we found that PIM suppressed VEGF expression in GIST cells by suppressing protein kinase D2 and hypoxia-inducible factor-1 alpha, which are both HSP90 client proteins. In conclusion, the combination of PIM and sunitinib is effective against imatinib-resistant GIST via the downregulation of KIT signaling and angiogenic signaling pathways.     

胃肠道间质瘤多因素预后分析

目的 探讨胃肠道间质瘤的生物学行为并对多因素进行预后分析。方法 对194例胃肠道间质瘤构建组织微阵列，采用免疫组织化学EnVision法检测胃肠道间质瘤组织中CD117、CD34、a-SMA、desmin、S-100、p53、Ki-67、PCNA的表达，结合随访资料，对其生物学行为进行分析。结果 全组1年、3年、5年生存率分别为93．5％、72．1％、63．2％。单因素分析，患者的预后与肿瘤部位、肿瘤大小、核分裂数、肿瘤有无坏死、出血、细胞密集程度、肿瘤细胞类型、核异型性、Ki-67标记指数、p53、性别等因素有关（P〈0．05）。初治患者预后同时与手术方式、周围脏器组织有无侵犯及黏膜有无受侵等因素有关。多因素分析显示肿瘤大小、核分裂数、坏死、周围组织侵犯、性别是影响预后的重要因素。结论影响胃肠道间质瘤的预后因素较多，胃间质瘤肿瘤直径〉10cm，核分裂数〉10个／50HPF，肿瘤有坏死，黏膜受侵提示肿瘤恶性度较高，Ki-67标记指数≥5％及p53蛋白（＋）有助于预测胃间质瘤侵袭行为；小肠间质瘤肿瘤直径〉5cm，均应高度警惕肿瘤的复发转移。CD34、SMA、desmin、PCNA、S-100蛋白阳性表达与预后无关。     

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

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.     

肠道胃肠间质瘤的临床病理改变

目的：了解肠道胃肠间质瘤（gastrintestinal stromal tumors GIST）的特殊临床病理改变。方法：收集31例肠道胃肠间质瘤的临床病理资料,每例常规光镜切片观察,作免疫组化CD34、CD117、SMA、S100、CKp标记。结果：肠道胃肠间质瘤临床症状以腹痛、肿块、便血为主。分布在十二指肠、小肠和直肠。以高危险度胃肠间质瘤为主。免疫组化标记：肿瘤细胞以CD34和CD117阳性为主。结论：肠道胃肠间质瘤临床症状与肠恶性肿瘤相似,诊断依据组织学改变和免疫组化标记,并以此判断肿瘤的危险度。     

Dysadherin expression in gastrointestinal stromal tumors (GISTs)

The purpose of this study was to detect the protein and mRNA expression of dysadherin and to investigate the clinical significance of dysadherin expression in gastrointestinal stromal tumors (GISTs).