Rectal Gastrointestinal Stromal Tumor Research Articles

A Novel Curative Treatment Strategy for Patients with Lower Grade Rectal Gastrointestinal Stromal Tumor: Chemoreduction Combined with Transanal Endoscopic Microsurgery.

A multimodal treatment has been applied for patients with rectal gastrointestinal stromal tumor (GIST) that represents 5% of the total localization. Meanwhile, transanal endoscopic microsurgery (TEM) offers a minimally invasive method for full-thickness tumor excision with negative margins and low morbidity. We report the single most extensive analysis of data from China to evaluate the feasibility and safety of the procedure combined with neoadjuvant imatinib therapy to treat patients with rectal GISTs. All the clinical data were obtained for patients who underwent the procedure in our hospital from February 2008 to May 2015, and the data were retrospectively analyzed. Full-thickness excision by TEM was performed on 25 patients with rectal GIST by using primary surgical excision, 8 of whom had received perioperative chemotherapy after histopathological confirmation under the care of medical oncologists. No obvious postoperative complications were observed. The average tumor downsizing ratio was 14.5%, which apparently enabled oversized tumors to be resected by TEM. The comparative risk did not increase during or after the procedure. We did not observe recurrence or metastasis in any of the 25 patients during the median 3-year follow-up period after the procedures. The perioperative imatinib treatment effectively allowed oversized rectal GIST tumors to be resected by TEM, and the procedures did not exhibit an increased risk. Exclusively, the TEM procedure with alternative neoadjuvant imatinib therapy is a feasible and safe modality for treating patients with rectal GISTs.

Subepithelial rectal gastrointestinal stromal tumor \u2013 the use of endoscopic ultrasound-guided fine needle aspiration to establish a definitive cytological diagnosis: a case report

BackgroundGastrointestinal stromal tumors are the most common mesenchymal neoplasms affecting the gastrointestinal tract. The stomach is the most common location to be affected, and the rectum one of the rarest, but the whole gastrointestinal tract remains susceptible. Gastrointestinal stromal tumors account for only 0.1% of rectal tumors. Currently, endoscopic ultrasound plays an essential role in the diagnostic process of gastrointestinal stromal tumors, especially when the affected sites have a worse outcome and higher morbidity rates.Case presentationWe describe the case of a 68-year-old white Japanese man with a history of long-term mild rectal pain and tenesmus. A digital rectal examination revealed a right palpable solid mass ranging from 3 to 7 cm from his anal verge. A colonoscopy was performed and showed a 5 cm elevated lesion covered by normal mucosa, located 4 cm above the pectineal line. Endoscopic ultrasound confirmed the diagnosis of a homogeneous hypoechoic mass with areas of necrosis as a rectal subepithelial lesion originating at the fourth layer (muscularis propria). He then underwent endoscopic ultrasound-guided fine needle aspiration of the lesion, followed by cytological and immunohistochemistry evaluation. The evaluation showed spindle and epithelioid cells of variable sizes, in fascicles separated by stroma, which reacted firmly and consistently to CD117/c-kit and CD34, and negative to desmin and S-100 protein. There was weak staining for nuclear Ki-67 in the tumor cells. A diagnosis of rectal gastrointestinal stromal tumor was confirmed. After a multidisciplinary meeting, an abdominoperineal resection of his rectum was performed. The pathology of the specimen confirmed the diagnosis of rectal gastrointestinal stromal tumor. He is now asymptomatic after 3 months’ follow-up and is on adjuvant therapy with a tyrosine-kinase inhibitor.ConclusionsGastrointestinal stromal tumors are rare tumors, and among the variety of primary location sites, the rectum is one of the rarest. The localization of this type of tumor has worse outcomes and higher morbidity rates. We report this rare case to emphasize the need for precise diagnosis and the important role of endoscopic ultrasound-guided fine needle aspiration in such situations.

Laparoscopic Total Pelvic Exenteration After Neoadjuvant Imatinib Therapy for Gastrointestinal Stromal Tumor of the Rectum: A Case Report

Total pelvic exenteration (TPE) may be the only curative procedure for locally advanced rectal gastrointestinal stromal tumor (GIST) that is contiguous with the adjacent organs and pelvic wall. There is no previous report of laparoscopic TPE for advanced rectal GIST. Here, we describe our experience of performing laparoscopic TPE on a locally advanced rectal GIST after neoadjuvant imatinib chemotherapy. A 62-year-old Japanese man was diagnosed with locally advanced rectal GIST that was contiguous with the seminal vesicles, prostate, and left pelvic sidewall. He received imatinib mesylate for 5 months, after which the mass had shrunk but was still contiguous with adjacent organs. We therefore needed to perform TPE, and we accomplished the operation laparoscopically. The total operative time was 540 minutes and estimated blood loss was 280 mL. There were no intraoperative complications and not required conversion to open surgery. The patient had his first stool on the first postoperative day and discharged on the 21st postoperative day with no major complication. Pathologic examination of the resected specimen revealed negative margins. The patient had further adjuvant imatinib chemotherapy and had no recurrence for 20 months postoperatively. Laparoscopic TPE appears to be minimally invasive surgery and safe in the present case of rectal GIST. This is the first report of a case in the world that underwent laparoscopic TPE for advanced rectal GIST.

Sphincter-saving resection by cluneal arched skin incision for a gastrointestinal stromal tumor (GIST) of the lower rectum: a case report

BackgroundPlanning the surgical strategy for a gastrointestinal stromal tumor (GIST) at the posterior wall of the lower rectum is difficult, as the procedures for the lower rectum are hampered by poor visualization and may cause anal dysfunction or discomfort. We report a novel procedure to resect a submucosal tumor of the rectum.Case presentationA 75-year-old woman presented with metrorrhagia. Endovaginal ultrasonography showed a low echoic tumor. Computed tomography showed an enhanced tumor, measuring 5.3 × 4.2 cm, behind the rectum. Magnetic resonance imaging revealed a submucosal tumor of the rectum, measuring 5.3 cm at its greatest dimension. Colonoscopy showed that the distal tumor margin was 1 cm above the dentate line. Core needle biopsy of the tumor revealed the rectal GIST. After receiving neoadjuvant imatinib treatment, the tumor size decreased to 3.5 cm. During the operation, we approached the rectum and resected the posterior rectal wall, including the 3.5 × 3.5 cm tumor with a safety margin, making an arched incision at the buttocks to form a skin flap with the patient in a jackknife position. The histopathological diagnosis was GIST of the rectum. Her anorectal sphincter function was well preserved. No recurrence was seen during the 2-year follow-up.ConclusionsThis novel approach improves the operative field visibility in resecting a tumor with a safety margin and preserves a patient’s anorectal sphincter function.

Imatinib mesylate-induced kidney injury in the treatment of a gastrointestinal stromal tumor

Gastrointestinal stromal tumors (GISTs) are a rare type of neoplasm arising within the gastrointestinal tract. Current treatment guidelines employ target-based therapy and adjuvant treatment with imatinib mesylate. We report a case of imatinib-induced renal injury in a 48-year-old male undergoing adjuvant chemotherapy after surgical resection of a rectal GIST. Upon initiation of imatinib therapy, the patient’s serum creatinine steadily rose and met criteria for kidney injury after twenty months of therapy. Drug discontinuation led to a normalization of renal function, but upon reinitiating therapy the serum creatinine sharply increased again. The patient’s recurrent acute renal injury led to indefinite drug discontinuation. Imatinib toxicities have been well studied; however, there are no reports to date noting its renal effects in the GIST patient population. This case report highlights imatinib as therapy for GISTs, describes an event of imatinib-induced renal injury, and reviews current treatment modalities.

Rectal GIST-Outcomes and viewpoint from a tertiary cancer center.

There is scarce data relating to methods to improve sphincter preservation in rectal gastrointestinal stromal tumor (GIST). Increasing the duration of neoadjuvant (NA) imatinib resulting in improved sphincter preservation rate has not been established. This retrospective analysis looks at the rates of sphincter preservation in rectal GIST with NA imatinib and effect of duration of NA imatinib on the same to find out optimum duration of NA with respect to sphincter preservation in rectal GIST patients. Twenty-three cases of GIST of lower third of rectum were treated at our centre from 2005 till 2015. NA imatinib was used in a dose of 400mg. Response evaluation was done every 3months with a pelvic magnetic resonance imaging. Surgical management was determined by a team of experienced gastrointestinal oncosurgeons. Five patients underwent upfront surgery which included local resection in four patients and abdominoperineal resection in one patient. NA imatinib was used in 69.5% (16/23) patients. Median duration of NA imatinib was 15months (3-84months). Amongst who underwent a sphincter-salvage surgery median duration of NA imatinib was 13months whereas 18months in patients who required a sphincter-sacrificing surgery (p=0.683). The radiologic response included partial response in 75% (12/16) patients, stable disease in 18.7% (3/16) and one with progressive disease. Definitive surgical resection was possible in 13 patients (81.3%) after NA imatinib. Median progression-free survival (PFS) was 120months in the whole cohort whereas median overall survival (OS) was not reached. Four-year estimated PFS and OS was 81% and 100%, respectively. Median disease-free survival in upfront surgery group vs. neoadjuvant imatinib group was 70 vs. 120months, respectively (p=0.039). Neoadjuvant imatinib appears to be a useful option in improving chances of sphincter preservation without adversely affecting the outcome. Use of neoadjuvant imatinib leads to improvement in progression-free survival in patients with GIST of lower third of the rectum.

Rectal gastrointestinal stromal tumor: a clinical and pathologic analysis

To investigate the clinicopathologic characteristics and therapy of rectal gastrointestinal stromal tumors (GISTs). Clinical findings, morphologic features, immunophenotype and prognosis of 53 cases (58 samples) of rectal GISTs were investigated. Thirty-three patients were male and 20 were female. The age of patients ranged from 19 to 81 years, with an average of 49.7 years. The main symptoms included rectal disorders in 29 patients and vaginal mass in 2 patients, while the tumors in 22 patients were found by routine physical examination. Thirty-five primary GISTs were resected completely without preoperative therapy, and thirteen tumors were resected after therapy of imatinib. Five tumors were recurrent. Imatinib therapy in 13 patients led to smaller and softer tumor mass grossly and decreased cellularity and marked degeneration histologically. Of the 35 primary rectal GISTs, there were 17 (48.6%), 6 (17.1%), 0(0), and 12 (34.3%) cases diagnosed as very low risk, low risk, medium risk, and high risk respectively. Eight cases had tumor of 1 cm or less in diameter. In the five recurrent cases, the tumors showed increased cellularity, mitotic figures, and Ki-67 index. Imatinib therapy led to smaller and softer tumor mass grossly and decreased cellularity and marked degeneration histologically. Immunohistochemical stains showed CD117, DOG1, and CD34 positivity, S-100 protein negativity and indefinite SMA stain. Rectal GISTs are rare tumors with a male predominance.Patients without obvious sypmtoms are found by themselves and by routine physical examination. The tumor diameter less than 2 cm is common while larger than 5 cm is few. Diagnosis of rectal GISTs is easily made by biopsy and patients often acquire preoperative therapy for preserving anal sphincter function.

Laparoscopic Management of Gastrointestinal Stromal Tumors: Nine Patients with Different Locations and Presentations: Retrospective Study

Background: Laparoscopic management of gastrointestinal stromal tumors (GISTs) is safe and effective. It is considered to be the preferred technique offered to the patient. Laparoscopic wedge resection has been widely accepted for small- and medium-sized GISTs. The use of laparoscopic approach should be based on a variety of factors including: patient characteristics, tumor size, and presence of invasion, location of tumor, surgeon and laparoscopic expertise. Patients and methods: Total number of nine patients with GISTs who presented to our unit from January 2010 till May 2015 were retrospectively reviewed. Patients’ demographics, clinical data, intraoperative and postoperative complications, and histopathological data were analyzed. Most lesions were resected via a wedge technique with closure of defect either by an endoscopic linear stapling device or intracorporeal suturing technique. Results: Nine patients who presented with GISTs underwent laparoscopic resection according to its position and size. The median age at diagnosis was 48 years old, and average tumor size was 4.2 cm with the largest tumor measuring 7.5 cm. There was no episode of tumor rupture or spillage and no major intraoperative or postoperative complications. All margins were negative, mean follow up was 14.4 (range 8.5–15.2) months. Majority of lesions were resected via laparoscopic wedge resection except one case (female patient aged 48 years old) that presented with GIST located at the gastric fundus , this patient underwent proximal (partial gastrectomy) and another case (adult male 26 years old) that presented with upper rectal GIST was managed via laparoscopic anterior resection. There was no evidence of metastasis or recurrence except in the patient who had been presented with rectal GIST. Conclusion: Laparoscopic resection is safe and effective for GISTs not exceeding 6 cm. Gastroesophageal junction and cardia GISTs require careful preoperative evaluation and planning to be removed safely. Laparoscopic removal is currently the surgical treatment of choice for patients with primary localized GISTs, and open surgery is not even considered unless there are contraindications to the laparoscopic approach

Neoadjuvant imatinib treatment and laparoscopic anus-preserving surgery for a large gastrointestinal stromal tumor of the rectum.

BackgroundResection of a gastrointestinal stromal tumor (GIST) of the rectum can be difficult because of the particular location in the pelvis, and a large rectal GIST often requires abdominoperineal resection. Recent reports demonstrate that neoadjuvant imatinib treatment improves surgical outcomes in patients with a rectal GIST, and there are only a few reports of the effectiveness of laparoscopic surgery for a rectal GIST.Case presentationA 46-year-old man was found to have a rectal GIST that measured 80 mm and was located on the anterior wall of the lower rectum. After 6 months treatment with imatinib, the tumor decreased in size to 37 mm, and laparoscopic low anterior resection was performed. The patient is currently alive without any evidence of recurrence 37 months after surgery.ConclusionsNeoadjuvant imatinib should be a treatment of choice for a large rectal GIST. When marked tumor shrinkage is achieved, laparoscopic surgery may be the preferred procedure.

Efficacy of erlotinib and imatinib in a patient with a rectal gastrointestinal stromal tumor and synchronous pulmonary adenocarcinoma: A case report

The synchronous existence of lung cancer and gastrointestinal stromal tumors (GIST) is considered to be extremely rare. To the best of our knowledge, this is the first report about the treatment of lung cancer and GIST with two kinds of molecular targeting drugs. An 83-year-old woman with a rectal GIST, which carried a c-kit mutation, and pulmonary adenocarcinoma, which exhibited an epidermal growth factor receptor (EGFR) mutation, was treated alternately with imatinib and erlotinib. Good control over both diseases was achieved for two years. The present case is not only of interest due to the rare co-occurrence of GIST and lung cancer, but also because it involved two tumors carrying different gene mutations, and both tumors were brought under control using different molecular targeting drugs.

Update on Laparoscopic Treatment of Gastrointestinal Stromal Tumors

Laparoscopic surgery and tyrosine kinase-inhibitor (TKI) therapy are frequently used to treat gastrointestinal stromal tumors (GISTs). The purpose of this review was to analyze the published data on minimally invasive treatment of GISTs, with special focus on tumor location and on the possible role of laparoscopy in association with imatinib mesylate therapy in the treatment of advanced forms. The MEDLINE® and Embase® databases were searched for potentially eligible English-language studies published through June 30, 2015. Laparoscopic surgery can be considered a treatment option for GISTs at all locations. Most gastric GISTs are suitable for laparoscopic wedge resection (44-100% in recent series). Gastric GISTs in difficult-to-treat areas may benefit from innovative approaches such as transgastric or intragastric resection. Few data are available for small-bowel and colonic GISTs, although laparoscopic resection complying with the oncologic principles seems feasible and safe with reported morbidity and mortality rates of 3.8-6.7% and 0%, respecively. Primary resection of large rectal GISTs carries a risk of recurrence up to 40%. To improve long-term results and reduce the invasiveness of surgery in this setting, as in other difficultto- treat areas, neoadjuvant imatinib therapy should be considered. In selected cases, the combination of imatinib mesylate therapy and laparoscopy can minimize surgical trauma. The appropriate adoption of laparoscopic surgery and TKI therapy can reduce surgical trauma and optimize long-term results.

Management of Gastrointestinal Stromal Tumors

Gastrointestinal stromal tumors (GISTs) are the most common tumors of mesenchymal origin in the gastrointestinal tract. These tumors are believed to arise from the interstitial cells of Cajal. The oncogenic activation of KIT or platelet-derived growth factor receptor–α is common to these tumors, and GISTS are considered to be a successful model for rational development of personalized treatments against oncogenic driver mutations in cancer. This review covers the epidemiology, etiology and genetics, pathophysiology and pathogenesis, diagnosis, differential diagnosis, treatment, complications, and prognosis of GISTs. Figures show KIT primary and secondary mutations, the clinical and molecular progression of GISTs, a contrast-enhanced computed tomographic scan showing a gastric GIST presenting as a huge abdominal mass, a magnetic resonance image showing a rectal GIST at baseline and responding to neoadjuvant imatinib after 8 months of treatment, and hematoxylin-eosin stain of a fusocellular and an epithelioid GIST. Tables list demographics and clinical characteristics, associated genetic syndromes, relevant differential diagnosis, risk stratification systems used in GIST, and the comparative activity of approved regimens for GIST. This review contains 5 highly rendered figures, 5 tables, and 74 references.

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

The aim of the present study was to assess the clinicopathological features and prognostic factors of primary small gastrointestinal stromal tumors (GISTs) outside the stomach. The clinical data, clinicopathological features and prognostic factors of 20 patients with a pathologically-confirmed diagnosis of non-gastric GIST that were treated at Liaoning Cancer Hospital & Institute between July 2006 and December 2013 were retrospectively analyzed. In total, 15 patients were male and 5 were female, with a median age of 58 years (range, 44–82 years). A change in bowel habits was the original symptom of rectal small GISTs in 6 out of 8 patients, while patients with small GISTs in other locations demonstrated no overt symptoms and the lesions were detected by systematic examinations of other diseases or abdominal surgical procedures performed on other organs. In total, 19 patients out of the total 20 patients underwent surgery, and 1 patient with rectal GIST received continuous oral imatinib mesylate (400 mg once a day) instead of undergoing surgery. The mean diameter of tumors was 1.55±0.54 cm (range, 0.3–2.0 cm) and the median was 1.70 cm. The pathomorphology of the lesions was mainly spindle cell, and immunohistochemistry revealed the expression rate of cluster of differentiation (CD)117, CD34 and discovered on GIST-1 were 85, 80 and 70%. According to the mitosis index, small rectal GISTs were more frequent compared with other positions (P<0.05), while the frequency of small GISTs >1 cm in size was not significantly different from the frequency of small GISTs ≤1 cm in size (P=0.995). All 20 patients were followed up, with a median follow-up duration of 49.5 months (range, 10.5–94.4 months). At the end of the follow-up period, tumor recurrence occurred in 5 patients and 1 patient succumbed following progression. According to the analysis of the tumor sites, the RFS time of patients with small rectal GISTs was significantly different than the RFS time in patients with small GISTs in other positions. The clinical symptoms of non-gastric small GISTs were not evident and were challenging to detect. Small GISTs, regardless of size, possessed malignant potential and once detected, GISTs should be surgically resected. Lesions located in the rectum demonstrated an increased degree of malignancy and were more likely to recur. The tumor size and Ki67 index could not be considered as prognostic factors of non-gastric small GISTs.

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

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

PWE-152 Retrospective observational cohort study of gastrointestinal stromal tumours (gists) in a uk regional cancer network

Introduction Gastrointestinal Stromal Tumours (GISTs) are tumours of mesenchymal origin that arise in the GI tract and account for approximately 0.1 to 3% of all gastrointestinal tumours. The aim of this study was to determine the relative incidence, clinical features and treatment outcome of GISTs diagnosed by a regional upper GI cancer network. Method One hundred and sixty one consecutive patients were identified through the regional upper GI cancer network. The median age was 66 (range 20–91) years; 86 male, 75 female. The primary outcome measure was survival. Results The anatomical distribution of the tumours was: gastric 74%; small bowel 15%; colorectal 3.8%; oesophageal 2.5%; unknown primary site 4.7%. Ninety-four (58.4%) underwent surgical resection. Thirteen were endoscopic (13.8%). Immunohistochemistry staining was performed on 46.6%, of which 89% were CD117 positive and 49.3% were CD34 positive. Malignant potential was recorded in 45.3% of cases: 12.4% benign; 14.3% low/low-intermediate; 8.7% intermediate; 3.7% high; 6.2% malignant. Overall 5- and 10- year survival was 79% and 53% respectively. Recurrent disease was identified in 6.8% of patients and progressive disease in 7.5%. Rectal and gastric GISTs had the poorest 5- and 10- year survival (p = 0.04). The median size of resected tumours was 5 cm (range 0.4 to 26 cm), and univariate analysis showed an association with survival (Chi 2 14.755, p = 0.005). On multivariable analysis, maximum dimension of resected tumour was the only variable independently associated with survival (HR 1.107, 95% CI 1.035–1.184, p = 0.03). Conclusion The majority of GISTs diagnosed were upper GI (76.5%). Five- and ten- year survival rates are longer than for other upper GI cancers and clinicians should be aware of this when counselling patients and planning management. Disclosure of interest None Declared.

Platelet-Derived Growth Factor Receptor-α Regulates Proliferation of Gastrointestinal Stromal Tumor Cells With Mutations in KIT by Stabilizing ETV1

In gastrointestinal muscles, v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT) is predominantly expressed by interstitial cells of Cajal (ICC) and platelet-derived growth factor receptor-α (PDGFRA) polypeptide is expressed by so-called fibroblast-like cells. KIT and PDGFRA have been reported to be coexpressed in ICC precursors and gastrointestinal stromal tumors (GISTs), which originate from the ICC lineage. PDGFRA signaling has been proposed to stimulate growth of GISTs that express mutant KIT, but the effects and mechanisms of selective blockade of PDGFRA are unclear. We investigated whether inhibiting PDGFRA could reduce proliferation of GIST cells with mutant KIT via effects on the KIT-dependent transcription factor ETV1. We studied 53 gastric, small intestinal, rectal, or abdominal GISTs collected immediately after surgery or archived as fixed blocks at the Mayo Clinic and University of California, San Diego. In human GIST cells carrying imatinib-sensitive and imatinib-resistant mutations in KIT, PDGFRA was reduced by RNA interference (knockdown) or inhibited with crenolanib besylate (a selective inhibitor of PDGFRA and PDGFRB). Mouse ICC precursors were retrovirally transduced to overexpress wild-type Kit. Cell proliferation was analyzed by methyltetrazolium, 5-ethynyl-2'-deoxyuridine incorporation, and Ki-67 immunofluorescence assays; we also analyzed growth of xenograft tumors in mice. Gastric ICC and ICC precursors, and their PDGFRA(+) subsets, were analyzed by flow cytometry and immunohistochemistry in wild-type, Kit(+/copGFP), Pdgfra(+/eGFP), and NOD/ShiLtJ mice. Immunoblots were used to quantify protein expression and phosphorylation. KIT and PDGFRA were coexpressed in 3%-5% of mouse ICC, 35%-44% of ICC precursors, and most human GIST samples and cell lines. PDGFRA knockdown or inhibition with crenolanib efficiently reduced proliferation of imatinib-sensitive and imatinib-resistant KIT(+)ETV1(+)PDGFRA(+) GIST cells (50% maximal inhibitory concentration= 5-32 nM), but not of cells lacking KIT, ETV1, or PDGFRA (50% maximal inhibitory concentration >230 nM). Crenolanib inhibited phosphorylation of PDGFRA and PDGFRB, but not KIT. However, Kit overexpression sensitized mouse ICC precursors to crenolanib. ETV1 knockdown reduced KIT expression and GIST proliferation. Crenolanib down-regulated ETV1 by inhibiting extracellular-signal-regulated kinase (ERK)-dependent stabilization of ETV1 protein and also reduced expression of KIT and PDGFRA. In KIT-mutant GIST, inhibition of PDGFRA disrupts a KIT-ERK-ETV1-KIT signaling loop by inhibiting ERK activation. The PDGFRA inhibitor crenolanib might be used to treat patients with imatinib-resistant, KIT-mutant GIST.

Gastrointestinal stromal tumors (GISTs) at uncommon locations: A large population based analysis

Sparse information is available about GISTs in uncommon locations. Our large database analysis aims to determine the characteristics of GISTs in the esophagus, colon and rectum and compare to gastric GISTs. The Surveillance Epidemiology and End Results (SEER) database was queried from 1990 to 2009 using CS SCHEMA v0203. Characteristics of each location were compared to gastric GISTs. 4411 GIST (29 esophageal, 2658 stomach, 1463 small intestine, 126 colonic, and 135 rectal) from 1990 to 2009 were identified. Univariate and multivariate predictors of worse disease specific survival in both the entire cohort and surgical resection group include older age, male gender, tumor size > 5 cm, no surgical intervention and anatomical location. Although less likely to undergo surgical resection, esophageal GIST (all patients and resected) had a comparable survival to gastric GIST. A higher proportion of colonic GISTs presented with distant disease and had a worse disease specific survival when compared to rectal GISTs. Our results show a rising incidence in GISTs and highlight the characteristics of GISTs based on anatomical location. In addition, this is the first study to demonstrate that colonic GISTs behave differently when compared to rectal GISTs and warrants further prospective evaluation.

Clinicopathologic, surgical characteristics and survival outcomes of rectal gastrointestinal stromal tumors.

Rectal gastrointestinal stromal tumors (GISTs) are rare, and limited information is available concerning their management and long-term outcomes. We retrospectively evaluated the clinicopathological characteristics, surgical management, and long-term outcomes of rectal GISTs from asingle institution.All surgically treated patients with rectal GISTS at the Department of General Surgery, West China Hospital, Sichuan University were identified between January 2005 and May 2014. The overall survival (OS) and disease-free survival (DFS) were assessed by the Kaplan-Meier method. Forty-five patients with rectal GISTs (33 males and 12 females) were identified. Patients presented with rectal bleeding (n=13; 28.9%) and altered bowel habits (n=11; 24.4%). The cohort study of 45 patients included 4 very low-risk, 10 low-risk, 1 intermediate-risk, and 30 high-risk patients. Atotal of 21, 13, and 11 patients underwent local resection (Group 1), abdominoperineal resection (Group 2), and super-low or low anterior resection (Group 3), respectively. Group 1 had asmaller tumor sizes and shorter distances from the anal verge compared with the other groups (P<0.05). The one-, three-, and five-year DFS rates for the entire cohort study were 90.4%, 69.3%, and 57.0%, respectively. High National Institutes of Health (NIH) risk categories (HR=1.62) were associated with low DFS rates (P=0.035). The DFS was significantly improved by imatinib mesylate (IM) adjuvant therapy in the high-risk subgroup (P=0.001). The type of surgery should be chosen based on the location and size of the rectal GISTs. Adjuvant IM therapy was associated with improved DFS in patients with high-risk tumors, and classification was strongly associated with the patient outcome.

Transsacral excision with pre-operative imatinib mesylate treatment and approach for gastrointestinal stromal tumors in the rectum: A report of two cases.

Gastrointestinal stromal tumors (GISTs) are rare in the rectum. Radical surgery, such as an abdominoperineal resection, is necessary for large rectal GISTs, which can result in the loss of function of involved organs. Imatinib mesylate can be used as perioperative therapy and may reduce tumor size, and it is now approved for use in the adjuvant therapy of locally resected anorectal GISTs. The present study describes two cases of large rectal GISTs, for which abdominoperineal resections were initially planned. The two patients received pre-operative imatinib mesylate treatment, and the therapeutic response was assessed by magnetic resonance imaging. Finally, transsacral local resection was successfully performed for these two GISTs. A macroscopically complete resection was achieved, and microscopically, the resection margin was negative. One patient experienced the complication of rectal leakage, which was successfully managed by drainage. No recurrence occurred in the two patients after more than two years. Pre-operative imatinib mesylate therapy with subsequent transsacral local resection for selected rectal GISTs is a feasible treatment modality and can prevent extended surgery.

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

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